Pyrazolyl substituted carbonic acid derivatives as modulators of the prostacyclin (pgi2) receptor useful for the treatment of disorders related thereto

ABSTRACT

Pyrazole derivatives of Formula Ia and pharmaceutical compositions thereof that modulate the activity of the PGI2 receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of: pulmonary arterial hypertension (PAH) and related disorders; platelet aggregation; coronary artery disease; myocardial infarction; transient ischemic attack; angina; stroke; ischemia-reperfusion injury; restenosis; atrial fibrillation; blood clot formation in an angioplasty or coronary bypass surgery individual or in an individual suffering from atrial fibrillation; atherosclerosis; atherothrombosis; asthma or a symptom thereof; a diabetic-related disorder such as diabetic peripheral neuropathy, diabetic nephropathy or diabetic retinopathy; glaucoma or other disease of the eye with abnormal intraocular pressure; hypertension; inflammation; psoriasis; psoriatic arthritis; rheumatoid arthritis; Crohn&#39;s disease; transplant rejection; multiple sclerosis; systemic lupus erythematosus (SLE); ulcerative colitis; ischemia-reperfusion injury; restenosis; atherosclerosis; acne; type 1 diabetes; type 2 diabetes; sepsis; and chronic obstructive pulmonary disorder (COPD).

FIELD OF THE INVENTION

The present invention relates to certain compounds of Formula Ia andpharmaceutical compositions thereof that modulate the activity of thePGI2 receptor. Compounds of the present invention and pharmaceuticalcompositions thereof are directed to methods useful in the treatment of:pulmonary arterial hypertension (PAH); idiopathic PAH; familial PAH; PAHassociated with: a collagen vascular disease, a congenital heartdisease, portal hypertension, HIV infection, ingestion of a drug ortoxin, hereditary hemorrhagic telangiectasia, splenectomy, pulmonaryveno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis(PCH); PAH with significant venous or capillary involvement; plateletaggregation; coronary artery disease; myocardial infarction; transientischemic attack; angina; stroke; ischemia-reperfusion injury;restenosis; atrial fibrillation; blood clot formation in an angioplastyor coronary bypass surgery individual or in an individual suffering fromatrial fibrillation; atherothrombosis; asthma or a symptom thereat adiabetic-related disorder such as diabetic peripheral neuropathy,diabetic nephropathy or diabetic retinopathy; glaucoma or other diseaseof the eye with abnormal intraocular pressure; hypertension;inflammation; psoriasis; psoriatic arthritis; rheumatoid arthritis;Crohn's disease; transplant rejection; multiple sclerosis; systemiclupus erythematosus (SLE); ulcerative colitis; atherosclerosis; acne;type 1 diabetes; type 2 diabetes; sepsis; and chronic obstructivepulmonary disorder (COPD).

BACKGROUND OF THE INVENTION

Prostacyclin (PGI2) is a lipid molecule derived from arachidonic acidthrough the cyclooxygenase pathway. It is a potent vasodilator,antiproliferative, anti-thrombotic and antiplatelet agent that mediatesits effects as an agonist of a G protein-coupled receptor (PGI2receptor; e.g., human PGI2 receptor, GenBank® Accession No. NP_000951and alleles thereof). It is known that the binding of PGI2 (or othersuch agonist) to the PGI2 receptor leads to coupling with the Gs proteinand increases intracellular cAMP levels. (See, e.g., Zhang et al., Arch.Biochem. Biophys., 2006, 454:80-88.)

Pulmonary arterial hypertension (PAH) is a life-threatening diseasecharacterized by a progressive pulmonary vasculopathy leading to rightventricular hypertrophy. Right heart failure occurs if left untreated.Prostacyclin, which has vasodilatory and antiproliferative effects onthe pulmonary vasculature has been found to be low in patients with PAHcompared with normal controls. Exogenous administration of prostacyclinor an analog of prostacyclin (i.e., an agonist of the PGI2 receptor) hasbecome an important strategy in the treatment of PAH. (See, e.g., Tuderet al., Am. J. Respir. Crit. Care. Med., 1999, 159:1925-1932; Humbert etal., J. Am. Coll. Cardiol., 2004, 43:13S-24S; Rosenzweig, Expert Opin.Emerging Drugs, 2006, 11:609-619; McLaughlin et al., Circulation, 2006,114:1417-1431; Rosenkranz, Clin. Res. Cardiol., 2007, 96:527-541;Driscoll et al., Expert Opin. Pharmacother., 2008, 9:65-81.)

Trepostinil and iloprost are FDA-approved analogs of prostacyclin which,like prostacyclin, are not orally-active. Beraprost is an orally-activeanalog of prostacyclin approved for the treatment of PAH in Japan, butit has failed registration for the treatment of PAH in Europe and in theUS. Of the three FDA-approved drugs, prostacyclin is the best studied inPAH patients. The approximate annual cost of treating PAH with thesedrugs is $25,000 to $200,000 depending on the dose. At present, manyexperts consider intravenous prostacyclin to be the most reliable agentfor managing the sickest PAH patients. Due to the short half-life ofprostacyclin, intravenous treatment is complicated by the need for acontinuous infusion. Patients are at risk for potentially fatal reboundpulmonary hypertension if the infusion is abruptly disrupted, as well assignificant risk of catheter-related complications including sepsis.(See, e.g., Rosenzweig, Expert Opin. Emerging Drugs, 2006, 11:609-619;Naeije et al., Expert Opin. Pharmacother., 2007, 8:2247-2265; Strauss etal., Clin. Chest. Med., 2007, 28:127-142; Driscoll et al., Expert Opin.Pharmacother., 2008, 9:65-81.)

There is considerable interest in developing prostacyclin analogs (i.e.,agonists of the PGI2 receptor) for use in the treatment of otherdiseases, such as atherothrombosis. Developing stable, orally-activeanalogs of prostacyclin (i.e., stable, orally-active agonists of thePGI2 receptor) is a rate-limiting step in achieving this goal (see,e.g., Arehart et al., Curr. Med. Chem., 2007, 14:2161-2169; Arehart etal., Circ. Res., 2008, 102(8), 986-93, as well as in the improvedmanagement of PAH.

SUMMARY OF THE INVENTION

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula Ia and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

-   -   R¹ is selected from: H and C₁-C₆ alkyl;    -   and    -   R², R³, and R⁴ are each independently selected from: H, C₁-C₆        alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl,        C₁-C₆ alkylthio, aryl, C₃-C₇ cycloalkyl and heteroaryl; wherein        said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆        alkylsulfonyl, C₁-C₆ alkylthio, aryl, C₃-C₇ cycloalkyl and        heteroaryl are each optionally substituted with one or more        groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆        alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, aryl,        amino, carboxamide, cyano, C₁-C₆ haloalkyl, halogen and hydroxy;    -   or    -   R² and R³ together with the pyrazole ring to which they are both        attached to form a tricyclic heteroaryl; and R⁴ is selected        from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆        alkylsulfonyl, C₁-C₆ alkylthio, aryl, C₃-C₇ cycloalkyl and        heteroaryl; wherein said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆        alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, aryl, C₃-C₇        cycloalkyl and heteroaryl are each optionally substituted with        one or more groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,        C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, aryl,        cyano, C₁-C₆ haloalkyl, halogen and hydroxy.

One aspect of the present invention pertains to methods for thetreatment of a PGI2 receptor mediated disorder in an individual,comprising administering to said individual in need thereof, atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of idiopathic PAH in an individual, comprising administeringto said individual in need thereof, a therapeutically effective amountof a compound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of familial PAH in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a collagen vascular disease in anindividual, comprising administering to said individual in need thereof,a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a collagen vascular disease selectedfrom: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE),rheumatoid arthritis, Takayasu's arteritis, polymyositis, anddermatomyositis in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a congenital heart disease in anindividual, comprising administering to said individual in need thereof,a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a congenital heart disease selectedfrom: atrial septic defect (ASD), ventricular septic defect (VSD) andpatent ductus arteriosus in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with portal hypertension in an individual,comprising administering to said individual in need thereof, atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with HIV infection in an individual,comprising administering to said individual in need thereof, atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with ingestion of a drug or toxin in anindividual, comprising administering to said individual in need thereof,a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with hereditary hemorrhagic telangiectasiain an individual, comprising administering to said individual in needthereof, a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with splenectomy in an individual,comprising administering to said individual in need thereof, atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with significant venous or capillaryinvolvement in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with pulmonary veno-occlusive disease (PVOD)in an individual, comprising administering to said individual in needthereof, a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with pulmonary capillary hemangiomatosis(PCH) in an individual, comprising administering to said individual inneed thereof, a therapeutically effective amount of a compound of thepresent invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of platelet aggregation in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of: coronary artery disease, myocardial infarction, transientischemic attack, angina, stroke, ischemia-reperfusion injury, restenosisor atrial fibrillation in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of blood clot formation in an angioplasty or coronary bypasssurgery individual comprising administering to said individual in needthereof, a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of blood clot formation in an individual suffering from atrialfibrillation comprising administering to said individual in needthereof, a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of atherosclerosis in an individual, comprising administeringto said individual in need thereof, a therapeutically effective amountof a compound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of atherothrombosis in an individual, comprising administeringto said individual in need thereof, a therapeutically effective amountof a compound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of asthma in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of a symptom of asthma in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of a diabetic-related disorder in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of diabetic peripheral neuropathy in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of diabetic nephropathy in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of diabetic retinopathy in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of glaucoma or other disease of the eye with abnormalintraocular pressure in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of hypertension in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of hypertension intended to confer protection against cerebralischemia in an individual, comprising administering to said individualin need thereof, a therapeutically effective amount of a compound of thepresent invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of inflammation in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of an inflammatory disease in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of an inflammatory disease selected from: psoriasis, psoriaticarthritis, rheumatoid arthritis, Crohn's disease, transplant rejection,multiple sclerosis, systemic lupus erythematosus (SLE), ulcerativecolitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne,type 1 diabetes, type 2 diabetes, sepsis, chronic obstructive pulmonarydisorder (COPD) and asthma in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods of modulatingthe activity of a PGI2 receptor by contacting the receptor with acompound of the present invention.

One aspect of the present invention pertains to methods of agonizing aPGI2 receptor by contacting the receptor with a compound of the presentinvention.

One aspect of the present invention pertains to methods for thetreatment of PAH selected from: idiopathic PAH; familial PAH; PAHassociated with a collagen vascular disease selected from: scleroderma,CREST syndrome, systemic lupus erythematosus (SLE), rheumatoidarthritis, Takayasu's arteritis, polymyositis, and dermatomyositis; PAHassociated with a congenital heart disease selected from: atrial septicdefect (ASD), ventricular septic defect (VSD) and patent ductusarteriosus in an individual; PAH associated with portal hypertension;PAH associated with HIV infection; PAH associated with ingestion of adrug or toxin; PAH associated with hereditary hemorrhagictelangiectasia; PAH associated with splenectomy; PAH associated withsignificant venous or capillary involvement; PAH associated withpulmonary veno-occlusive disease (PVOD); and PAH associated withpulmonary capillary hemangiomatosis (PCH) in an individual comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of a disorder selected from: platelet aggregation, coronaryartery disease, myocardial infarction, transient ischemic attack,angina, stroke, ischemia-reperfusion injury, restenosis, atrialfibrillation, blood clot formation, atherosclerosis, atherothrombosis,asthma, a symptom of asthma, a diabetic-related disorder, diabeticperipheral neuropathy, diabetic nephropathy, diabetic retinopathy,glaucoma or other disease of the eye with abnormal intraocular pressure,hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoidarthritis, Crohn's disease, transplant rejection, multiple sclerosis,systemic lupus erythematosus (SLE), ulcerative colitis,ischemia-reperfusion injury, restenosis, atherosclerosis, acne, type 1diabetes, type 2 diabetes, sepsis and chronic obstructive pulmonarydisorder (COPD) in an individual comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a PGI2 receptor mediated disorder.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of idiopathic PAH.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of familial PAH.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with collagen vascular disease.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with a collagen vascular disease selectedfrom: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE),rheumatoid arthritis, Takayasu's arteritis, polymyositis, anddermatomyositis.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with a congenital heart disease.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with a congenital heart disease selectedfrom: atrial septic defect (ASD), ventricular septic defect (VSD) andpatent ductus arteriosus.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with portal hypertension.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with HIV infection.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with ingestion of a drug or toxin.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with hereditary hemorrhagic telangiectasia.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with splenectomy.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with significant venous or capillaryinvolvement.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with pulmonary veno-occlusive disease(PVOD).

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with pulmonary capillary hemangiomatosis(PCH).

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of platelet aggregation.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a PGI2 receptor mediated disorder selected from: coronaryartery disease, myocardial infarction, transient ischemic attack,angina, stroke, ischemia-reperfusion injury, restenosis and atrialfibrillation.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of blood clot formation in an angioplasty or coronary bypasssurgery individual.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of blood clot formation in an individual suffering from atrialfibrillation.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of atherosclerosis.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of atherothrombosis.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of asthma.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a symptom of asthma.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a diabetic-related disorder.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of diabetic peripheral neuropathy.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of diabetic nephropathy.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of diabetic retinopathy.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of glaucoma or other disease of the eye with abnormalintraocular pressure.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of hypertension.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of hypertension intended to confer protection against cerebralischemia.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of inflammation.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of an inflammatory disease.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of an inflammatory disease selected from: psoriasis, psoriaticarthritis, rheumatoid arthritis, Crohn's disease, transplant rejection,multiple sclerosis, systemic lupus erythematosus (SLE), ulcerativecolitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne,type 1 diabetes, type 2 diabetes, sepsis, chronic obstructive pulmonarydisorder (COPD) and asthma.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for modulatingthe activity of a PGI2 receptor.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for agonizing aPGI2 receptor.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH selected from: idiopathic PAH; familial PAH; PAHassociated with a collagen vascular disease selected from: scleroderma,CREST syndrome, systemic lupus erythematosus (SLE), rheumatoidarthritis, Takayasu's arteritis, polymyositis, and dermatomyositis; PAHassociated with a congenital heart disease selected from: atrial septicdefect (ASD), ventricular septic defect (VSD) and patent ductusarteriosus in an individual; PAH associated with portal hypertension;PAH associated with HIV infection; PAH associated with ingestion of adrug or toxin; PAH associated with hereditary hemorrhagictelangiectasia; PAH associated with splenectomy; PAH associated withsignificant venous or capillary involvement; PAH associated withpulmonary veno-occlusive disease (PVOD); and PAH associated withpulmonary capillary hemangiomatosis (PCH).

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a disorder selected from: platelet aggregation, coronaryartery disease, myocardial infarction, transient ischemic attack,angina, stroke, ischemia-reperfusion injury, restenosis, atrialfibrillation, blood clot formation, atherosclerosis, atherothrombosis,asthma, a symptom of asthma, a diabetic-related disorder, diabeticperipheral neuropathy, diabetic nephropathy, diabetic retinopathy,glaucoma or other disease of the eye with abnormal intraocular pressure,hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoidarthritis, Crohn's disease, transplant rejection, multiple sclerosis,systemic lupus erythematosus (SLE), ulcerative colitis,ischemia-reperfusion injury, restenosis, atherosclerosis, acne, type 1diabetes, type 2 diabetes, sepsis and chronic obstructive pulmonarydisorder (COPD).

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of the human or animal bodyby therapy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of a PGI2 receptor mediateddisorder.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of idiopathic PAH.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of familial PAH

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with acollagen vascular disease.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with acollagen vascular disease selected from: scleroderma, CREST syndrome,systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu'sarteritis, polymyositis, and dermatomyositis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with acongenital heart disease.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with acongenital heart disease selected from: atrial septic defect (ASD),ventricular septic defect (VSD) and patent ductus arteriosus.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with portalhypertension.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with HIVinfection.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withingestion of a drug or toxin.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withhereditary hemorrhagic telangiectasia.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withsplenectomy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withsignificant venous or capillary involvement.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withpulmonary veno-occlusive disease (PVOD).

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withpulmonary capillary hemangiomatosis (PCH).

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of platelet aggregation.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of: coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke,ischemia-reperfusion injury, restenosis or atrial fibrillation.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of blood clot formation in anangioplasty or coronary bypass surgery individual.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of blood clot formation in anindividual suffering from atrial fibrillation.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of atherosclerosis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of atherothrombosis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of asthma.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of a symptom of asthma.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of a diabetic-relateddisorder.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of diabetic peripheralneuropathy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of diabetic nephropathy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of diabetic retinopathy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of glaucoma or other diseaseof the eye with abnormal intraocular pressure.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of hypertension.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of hypertension intended toconfer protection against cerebral ischemia.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of inflammation.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of an inflammatory disease.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of an inflammatory diseaseselected from: psoriasis, psoriatic arthritis, rheumatoid arthritis,Crohn's disease, transplant rejection, multiple sclerosis, systemiclupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusioninjury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2diabetes, sepsis, chronic obstructive pulmonary disorder (COPD) andasthma.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of modulating the activity of a PGI2receptor.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of agonizing a PGI2 receptor.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH selected from:idiopathic PAH; familial PAH; PAH associated with a collagen vasculardisease selected from: scleroderma, CREST syndrome, systemic lupuserythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis,polymyositis, and dermatomyositis; PAH associated with a congenitalheart disease selected from: atrial septic defect (ASD), ventricularseptic defect (VSD) and patent ductus arteriosus in an individual; PAHassociated with portal hypertension; PAH associated with HIV infection;PAH associated with ingestion of a drug or toxin; PAH associated withhereditary hemorrhagic telangiectasia; PAH associated with splenectomy;PAH associated with significant venous or capillary involvement; PAHassociated with pulmonary veno-occlusive disease (PVOD); and PAHassociated with pulmonary capillary hemangiomatosis (PCH).

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of a disorder selected from:platelet aggregation, coronary artery disease, myocardial infarction,transient ischemic attack, angina, stroke, ischemia-reperfusion injury,restenosis, atrial fibrillation, blood clot formation, atherosclerosis,atherothrombosis, asthma, a symptom of asthma, a diabetic-relateddisorder, diabetic peripheral neuropathy, diabetic nephropathy, diabeticretinopathy, glaucoma or other disease of the eye with abnormalintraocular pressure, hypertension, inflammation, psoriasis, psoriaticarthritis, rheumatoid arthritis, Crohn's disease, transplant rejection,multiple sclerosis, systemic lupus erythematosus (SLE), ulcerativecolitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne,type 1 diabetes, type 2 diabetes, sepsis and chronic obstructivepulmonary disorder (COPD).

One aspect of the present invention pertains to compounds for preparinga composition comprising admixing a compound of the present inventionand a pharmaceutically acceptable carrier.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of an experiment which measured the ability ofCompound 14 to inhibit the right ventricle hypertrophic response toMCT-induced pulmonary arterial hypertension in rat.

FIG. 2 shows the results of an experiment which measured the ability ofCompound 31 to inhibit the right ventricle hypertrophic response toMCT-induced pulmonary arterial hypertension in rat.

FIG. 3 depicts a general method for the preparation of compounds of thepresent invention. First, cyclohexane-1,4-dicarboxylic acid isesterified and then reduced to give the corresponding diol. The diol ismono-alkylated with tert-butyl bromoacetate and the free hydroxyl isactivated as a sulfonate ester. Coupling of the sulfonate ester with apyrazole followed by acid hydrolysis affords compounds of Formula Ia.

FIG. 4 depicts an alternative general method for the preparation ofcompounds of the present invention. In this method the sulfonate estershown in FIG. 3 is reacted in the presence of a base with a pyrazolebearing a halogen at a position equivalent to R³. The product thenundergoes a Suzuki coupling with a boronic acid derivative and then acidhydrolysis affords compounds of Formula Ia.

FIG. 5 depicts a method of preparing an intermediate useful in thesynthesis of certain dihydroxy compounds of the present invention.First, a 3-oxobutanoyl derivative is reacted with allyl bromide in thepresence of base to give a 3-oxohept-6-enoyl derivative. Reaction withhydrazine hydrate gives a 5-(but-3-enyl)-1H-pyrazole which is convertedto the diol with AD-mix-β and then protected with 2,2-dimethoxypropane.

FIG. 6 depicts a number of methods for synthesizing intermediates usefulin the preparation of compounds of the present invention. In the firstof these methods, a ketone derivative is reacted with carbon disulfidein the presence of base, followed by an alkyl halide, followed byhydrazine hydrate to give a 2-(alkylthio)-substituted pyrazoleintermediate. In the second of these methods, a methyl ketone is reactedwith carbon disulfide in the presence of base, followed by an alkylhalide, followed by hydrazine hydrate to give a2-(alkylthio)-substituted pyrazole intermediate in which R³ is hydrogen.This may then be converted to the corresponding iodide by treatment withsodium iodide and base. In the third of these methods, a3-oxo-3-propoxypropanoyl derivative is treated with hydrazine hydrate toafford a 1H-pyrazol-5(4H)-one. Mitsunobu reaction followed bybromination affords 2-alkoxy-3-bromo pyrazole intermediates. In thefourth of these methods, a methyl ketone is reacted with an acidchloride in the presence of base, then hydrazine hydrate and finallybromine or sodium iodide in the presence of base to give 3-halo-2-alkyl-or 3-halo-2-cycloalkyl-pyrazole intermediates.

FIG. 7 depicts three methods for the synthesis of certain intermediatesuseful in the preparation of compounds of the present invention. In thefirst of these methods a ketone derivative is reacted first with carbondisulfide and methylene bromide in the presence of base, then hydrazinehydrate and finally bromo acetonitrile to give a2-(cyanomethylthio)-pyrazole intermediate. In the second of thesemethods, a ketone derivative is converted to a2-(tetrahydro-2H-pyran-2-yloxy)ethylthio-pyrazole. The transformationmay be accomplished by either reaction with carbon disulfide, methylenebromide and base, followed by hydrazine hydrate, followed by2-(2-bromoethoxy)tetrahydro-2H-pyran, or reaction with carbon disulfideand base, then 2-(2-bromoethoxy)tetrahydro-2H-pyran and finallyhydrazine hydrate. The third method describes the preparation ofsubstituted 4,5-dihydro-3H-benzo[e]indazole and1,8-dihydroindeno[2,1-c]pyrazole intermediates from3,4-dihydronaphthalen-2(1H)-one or 1H-inden-2(3H)-one respectively viareaction with an acid chloride in the presence of base followed byreaction with hydrazine hydrate.

FIG. 8 depicts a method of preparing certain di-substituted compounds ofthe present invention. β-Keto aldehydes derived from chalcone epoxidesby Lewis acid-catalyzed rearrangement are reacted with hydrazine hydrateto give di-substituted pyrazoles. These are reacted with the sulfonateesters described in FIG. 3 to give di-substituted compounds of FormulaIa as mixtures of regioisomers.

FIG. 9 depicts a general method of preparing compounds of the presentinvention. Starting from 4-(hydroxymethyl)cyclohexanecarboxylic acid theacid group is esterified and the alcohol is protected with a benzylgroup. Next, the ester is reduced and reoxidized to the aldehyde. Thealdehyde undergoes reductive amination to give a Boc-protected hydrazinewhich is subsequently deprotected and then coupled with an aldehyde togive an imine. This is reacted with a nitroalkene is the presence ofbase to form the pyrazole ring. Next, the benzyl protecting group isremoved reductively, the alcohol is reacted with tert-butyl2-diazoacetate in the presence of rhodium acetate to give the2-tert-butoxy-2-oxoethoxy derivative which is finally converted to acompound of Formula Ia by treatment with acid.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For clarity and consistency, the following definitions will be usedthroughout this patent document.

The term “agonists” is intended to mean moieties that interact andactivate the receptor, such as, the PGI2 receptor and initiate aphysiological or pharmacological response characteristic of thatreceptor. For example, when moieties activate the intracellular responseupon binding to the receptor, or enhance GTP binding to membranes.

The term “contact or contacting” is intended to mean bringing theindicated moieties together, whether in an in vitro system or an in vivosystem. Thus, “contacting” a PGI2 receptor with a compound of theinvention includes the administration of a compound of the presentinvention to an individual, preferably a human, having a PGI2 receptor,as well as, for example, introducing a compound of the invention into asample containing a cellular or more purified preparation containing aPGI2 receptor.

The term “hydrate” as used herein means a compound of the invention or asalt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

The terms “including” and “such as” are illustrative and not limitative.

The term “in need of treatment” and the term “in need thereof,” whenreferring to treatment are used interchangeably to mean a judgment madeby a caregiver (e.g. physician, nurse, nurse practitioner, etc. in thecase of humans; veterinarian in the case of animals, including non-humanmammals) that an individual or animal requires or will benefit fromtreatment. This judgment is made based on a variety of factors that arein the realm of a caregiver's expertise, but that includes the knowledgethat the individual or animal is ill, or will become ill, as the resultof a disease, condition or disorder that is treatable by the compoundsof the invention. Accordingly, the compounds of the invention can beused in a protective or preventive manner; or compounds of the inventioncan be used to alleviate, inhibit or ameliorate the disease, conditionor disorder.

The term “individual” is intended to mean any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates and most preferably humans.

The term “modulate or modulating” is intended to mean an increase ordecrease in the amount, quality, response or effect of a particularactivity, function or molecule.

The term “pharmaceutical composition” is intended to mean a compositioncomprising at least one active ingredient; including but not limited to,salts, solvates and hydrates of compounds of the present invention;whereby the composition is amenable to investigation for a specified,efficacious outcome in a mammal (for example, without limitation, ahuman). Those of ordinary skill in the art will understand andappreciate the techniques appropriate for determining whether an activeingredient has a desired efficacious outcome based upon the needs of theartisan.

The term “solvate” as used herein means a compound of the invention or asalt, thereof, that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for administration to humans in trace amounts.

The term “therapeutically effective amount” is intended to mean theamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician or caregiver; or in an individual, whichincludes one or more of the following:

(1) Preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) Inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and

(3) Ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

Chemical Group, Moiety or Radical

The term “AD-mix-α” is intended to mean a mixture of potassium osmate,potassium ferricyanide, potassium carbonate and hydroquinine1,4-phthalazinediyl diether.

The term “AD-mix-β” is intended to mean a mixture of potassium osmate,potassium ferricyanide, potassium carbonate and hydroquinidine1,4-phthalazinediyl diether.

The term “C₁-C₆ alkoxy” is intended to mean a C₁-C₆ alkyl radical, asdefined herein, attached directly to an oxygen atom. Some embodimentsare 1 to 5 carbons; some embodiments are 1 to 4 carbons; someembodiments are 1 to 3 carbons; and some embodiments are 1 or 2 carbons.Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,t-butoxy, isobutoxy, sec-butoxy and the like.

The term “C₁-C₆ alkyl” is intended to mean a straight or branched carbonradical containing 1 to 6 carbons. Some embodiments are 1 to 5 carbons.Some embodiments are 1 to 4 carbons. Some embodiments are 1 to 3carbons. Some embodiments are 1 or 2 carbons. Some embodiments are 1carbon. Examples of an alkyl include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl,pentyl, isopentyl, t-pentyl, neo-pentyl, 1-methylbutyl [i.e.,—CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e., —CH₂CH(CH₃)CH₂CH₃], n-hexyl andthe like.

The term “C₁-C₆ alkylsulfinyl” is intended to mean a C₁-C₆ alkyl radicalattached to the sulfur of a sulfoxide radical having the formula: —S(O)—wherein the alkyl radical has the same definition as described herein.Examples include, but are not limited to, methylsulfinyl, ethylsulfinyl,n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl,isobutylsulfinyl, t-butylsulfinyl, and the like.

The term “C₁-C₆ alkylsulfonyl” is intended to mean a C₁-C₆ alkyl radicalattached to the sulfur of a sulfone radical having the formula: —S(O)₂—wherein the alkyl radical has the same definition as described herein.Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl,n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,isobutylsulfonyl, t-butylsulfonyl, and the like.

The term “C₁-C₆ alkylthio” is intended to mean a C₁-C₆ alkyl radicalattached to a sulfur atom (i.e., —S—) wherein the alkyl radical has thesame definition as described herein. Examples include, but are notlimited to, methylsulfanyl (i.e., CH₃S—), ethylsulfanyl,n-propylsulfanyl, iso-propylsulfanyl, n-butylsulfanyl,sec-butylsulfanyl, iso-butylsulfanyl, t-butylsulfanyl, and the like.

The term “amino” is intended to mean the group —NH₂.

The term “aryl” is intended to mean an aromatic ring radical containing6 to 10 ring carbons. Examples include phenyl and naphthyl. In someembodiments aryl is intended to mean phenyl.

The term “carboxamide” is intended to mean the group —CONH₂.

The term “cyano” is intended to mean the group —CN.

The term “C₃-C₇ cycloalkyl” is intended to mean a saturated ring radicalcontaining 3 to 7 carbons. Some embodiments contain 3 to 6 carbons. Someembodiments contain 3 to 5 carbons Some embodiments contain 5 to 7carbons. Some embodiments contain 3 to 4 carbons. Examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and thelike.

The term “C₁-C₆ haloalkyl” is intended to mean a C₁-C₆ alkyl group,defined herein, wherein the alkyl is substituted with one halogen up tofully substituted and a fully substituted C₁-C₆ haloalkyl can berepresented by the formula C_(n)L_(2n+1) wherein L is a halogen and “n”is 1, 2, 3, 4, 5 or 6. When more than one halogen is present then theymay be the same or different and selected from the group consisting ofF, Cl, Br and I, preferably F. Some embodiments are 1 to 5 carbons, someembodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons, andsome embodiments are 1 or 2 carbons. Examples of haloalkyl groupsinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl,pentafluoroethyl and the like.

The term “halogen” or “halo” is intended to mean to a fluoro, chloro,bromo or iodo group.

The term “heteroaryl” is intended to mean an aromatic ring systemcontaining 5 to 14 aromatic ring atoms that may be a single ring, twofused rings or three fused rings wherein at least one aromatic ring atomis a heteroatom selected from, but not limited to, the group consistingof O, S and N wherein the N can be optionally substituted with H, C₁-C₄acyl or C₁-C₄ alkyl. Some embodiments contain 5 to 6 ring atoms forexample furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyland the like. Some embodiments contain 8 to 14 ring atoms for examplecarbazolyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl,isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl,benzothienyl, benzofuranyl, isobenzofuran and the like.

The term “hydroxyl” or “hydroxy” is intended to mean the group —OH.

The term “MP-carbonate” is intended to mean macroporous triethylammoniummethylpolystyrene carbonate.

Compounds of the Invention One aspect of the present invention pertainsto certain compounds as shown in Formula Ia:

and pharmaceutically acceptable salts, solvates and hydrates thereof;

wherein R¹, R², R³ and R⁴ have the same definitions as described herein,supra and infra.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g.,R¹, R², R³ and R⁴) contained within the generic chemical formulaedescribed herein, for example, Ta, Ic, Ie, Ig, Ii, etc., arespecifically embraced by the present invention just as if each and everycombination was individually explicitly recited, to the extent that suchcombinations embrace compounds that result in stable compounds (i.e.,compounds that can be isolated, characterized and tested for biologicalactivity). In addition, all subcombinations of the chemical groupslisted in the embodiments describing such variables, as well as allsubcombinations of uses and medical indications described herein, arealso specifically embraced by the present invention just as if each andevery subcombination of chemical groups and subcombination of uses andmedical indications was individually and explicitly recited herein.

As used herein, “substituted” indicates that at least one hydrogen atomof the chemical group is replaced by a non-hydrogen substituent orgroup, the non-hydrogen substituent or group can be monovalent ordivalent. When the substituent or group is divalent, then it isunderstood that this group is further substituted with anothersubstituent or group. When a chemical group herein is “substituted” itmay have up to the full valance of substitution; for example, a methylgroup can be substituted by 1, 2, or 3 substituents, a methylene groupcan be substituted by 1 or 2 substituents, a phenyl group can besubstituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can besubstituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.Likewise, “substituted with one or more substituents” refers to thesubstitution of a group with one substituent up to the total number ofsubstituents physically allowed by the group. Further, when a group issubstituted with more than one group they can be identical or they canbe different.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers and the like. Tautomeric forms can be in equilibriumor sterically locked into one form by appropriate substitution. It isunderstood that the various tautomeric forms are within the scope of thecompounds of the present invention.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates and/or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include deuterium and tritium.

It is understood and appreciated that compounds of Formula Ia andformulae related thereto may have one or more chiral centers andtherefore can exist as enantiomers and/or diastereoisomers. Theinvention is understood to extend to and embrace all such enantiomers,diastereoisomers and mixtures thereof, including but not limited toracemates. It is understood that compounds of Formula Ia and formulaeused throughout this disclosure are intended to represent all individualenantiomers and mixtures thereof, unless stated or shown otherwise.

It is understood and appreciated that compounds of Formula Ia exist asmeso isomers. Such meso isomers may be referred to as cis and trans.Certain cis meso isomers of compounds of Formula Ia are named hereinusing the prefix (1s,4s) and certain trans meso isomers of compounds ofFormula Ia are named herein using the prefix (1r,4r) as shown below.

It is further understood and appreciated that certain compounds ofFormula Ia bear a 3,4-dihydroxybutyl substituent on the pyrazole ring.When the absolute stereochemistry of the dihydroxybutyl group is (S)then certain cis compounds of Formula Ia are named herein using theprefix (1R,4s). When the absolute stereochemistry of the dihydroxybutylgroup is (R) then certain cis compounds of Formula Ia are named hereinusing the prefix (1S,4s) as shown below.

It is well understood and appreciated in the art that pyrazoles canexist in various tautomeric forms. Two possible tautomeric forms ofcertain intermediates useful in the preparation of compounds of thepresent invention are illustrated below:

It is further understood that tautomeric forms can also havecorresponding nomenclature for each represented tautomer. The presentinvention includes all tautomers and the various nomenclaturedesignations.

The Group R¹:

In some embodiments, R¹ is selected from: H and C₁-C₆ alkyl.

In some embodiments, R¹ is H.

In some embodiments, R¹ is C₁-C₆ alkyl.

In some embodiments, R¹ is methyl.

The Group R²:

In some embodiments, R² is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl,C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, aryl andC₃-C₇ cycloalkyl; wherein said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, aryl and C₃-C₇cycloalkyl are each optionally substituted with one or more groupsselected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylthio, amino, carboxamide, cyano, halogen andhydroxy.

In some embodiments, R² is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl,C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, aryl andC₃-C₇ cycloalkyl; wherein said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, aryl and C₃-C₇cycloalkyl are each optionally substituted with one or more groupsselected from: amino, carboxamide, chloro, cyano, ethoxy, fluoro,hydroxy, methoxy, methyl, methylsulfinyl, methylsulfonyl and methylthio.

In some embodiments, R² is selected from: H, butyl, cyclopropyl, ethoxy,ethyl, ethylsulfinyl, ethylthio, isopropyl, methoxy, methyl,methylsulfinyl, methylsulfonyl, methylthio, phenyl, propyl andpropylthio; wherein said butyl, cyclopropyl, ethoxy, ethyl,ethylsulfinyl, ethylthio, isopropyl, methoxy, methyl, methylsulfinyl,methylsulfonyl, methylthio, phenyl, propyl and propylthio are eachoptionally substituted with one or more groups selected from: amino,carboxamide, chloro, cyano, ethoxy, fluoro, hydroxy, methoxy, methyl,methylsulfinyl, methylsulfonyl and methylthio.

In some embodiments, R² is selected from: H, 2-(methylsulfinyl)ethyl,2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2,3-difluorophenyl,2-aminoethylthio, 2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 2-hydroxyethyl,2-hydroxyethylsulfinyl, 2-hydroxyethylthio, 2-methoxyethyl,2-methoxyethylthio, 3,4-difluorophenyl, 3,4-dihydroxybutyl,3-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-hydroxypropylthio, 3-methoxyphenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-methoxyphenyl, cyanomethoxy, cyanomethylthio, cyclopropyl, ethoxy,ethyl, ethylthio, isopropyl, methyl, methylsulfinyl, methylsulfonyl,methylthio, m-tolyl, n-propyl, phenyl and trifluoromethyl.

In some embodiments, R² is selected from: H, 2-(methylsulfinyl)ethyl,2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2,3-difluorophenyl,2-aminoethylthio, 2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 2-hydroxyethyl,2-hydroxyethylsulfinyl, 2-hydroxyethylthio, 2-methoxyethyl,2-methoxyethylthio, 3,4-difluorophenyl, 3,4-dihydroxybutyl,3-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-hydroxypropylthio, 3-methoxyphenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-methoxyphenyl, cyanomethoxy, cyanomethylthio, cyclopropyl, ethoxy,ethyl, ethylthio, isopropyl, methyl, methylsulfinyl, methylsulfonyl,methylthio, m-tolyl, n-propyl, phenyl, p-tolyl and trifluoromethyl.

In some embodiments, R² is H.

In some embodiments, R² is 2-(methylsulfinyl)ethyl.

In some embodiments, R² is 2-(methylsulfonyl)ethyl.

In some embodiments, R² is 2-(methylthio)ethyl.

In some embodiments, R² is 2,3-difluorophenyl.

In some embodiments, R² is 2-aminoethylthio.

In some embodiments, R² is 2-amino-2-oxoethoxy.

In some embodiments, R² is 2-cyanoethyl.

In some embodiments, R² is 2-ethoxyethylthio.

In some embodiments, R² is 2-fluoro-4-methoxyphenyl.

In some embodiments, R² is 2-fluorophenyl.

In some embodiments, R² is 2-hydroxyethyl.

In some embodiments, R² is 2-hydroxyethylsulfinyl.

In some embodiments, R² is 2-hydroxyethylthio.

In some embodiments, R² is 2-methoxyethyl.

In some embodiments, R² is 2-methoxyethylthio.

In some embodiments, R² is 3,4-difluorophenyl.

In some embodiments, R² is 3,4-dihydroxybutyl.

In some embodiments, R² is 3-chloro-2-fluorophenyl.

In some embodiments, R² is 3-fluoro-5-methoxyphenyl.

In some embodiments, R² is 3-fluorophenyl.

In some embodiments, R² is 3-hydroxypropyl.

In some embodiments, R² is 3-hydroxypropylthio.

In some embodiments, R² is 3-methoxyphenyl.

In some embodiments, R² is 4-chloro-3-fluorophenyl.

In some embodiments, R² is 4-chlorophenyl.

In some embodiments, R² is 4-fluorophenyl.

In some embodiments, R² is 4-chlorophenyl.

In some embodiments, R² is 4-chlorophenyl.

In some embodiments, R² is 4-methoxyphenyl.

In some embodiments, R² is cyanomethoxy.

In some embodiments, R² is 4-chlorophenyl.

In some embodiments, R² is cyanomethylthio.

In some embodiments, R² is cyclopropyl.

In some embodiments, R² is ethoxy.

In some embodiments, R² is ethyl.

In some embodiments, R² is ethylthio.

In some embodiments, R² is isopropyl.

In some embodiments, R² is methyl.

In some embodiments, R² is methylsulfinyl.

In some embodiments, R² is methyl.

In some embodiments, R² is methylsulfonyl.

In some embodiments, R² is methylthio.

In some embodiments, R² is m-tolyl.

In some embodiments, R² is n-propyl.

In some embodiments, R² is phenyl.

In some embodiments, R² is p-tolyl.

In some embodiments, R² is trifluoromethyl.

The Group R³:

In some embodiments, R³ is selected from: C₁-C₆ alkyl, aryl andheteroaryl; wherein said C₁-C₆ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more groups selected from: C₁-C₆alkoxy, C₁-C₆ alkyl, aryl, cyano, C₁-C₆ haloalkyl, halogen and hydroxy.

In some embodiments, R³ is selected from: C₁-C₆ alkyl, aryl andheteroaryl; wherein said C₁-C₆ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more groups selected from: chloro,cyano, ethoxy, fluoro, hydroxy, isopropoxy, methoxy, methyl, phenyl andtrifluoromethyl.

In some embodiments, R³ is selected from: furan-2-yl, methyl, phenyl,pyridin-3-yl, pyridin-4-yl, thiophen-2-yl and thiophen-3-yl; whereinsaid furan-2-yl, methyl, phenyl, pyridin-3-yl, pyridin-4-yl,thiophen-2-yl and thiophen-3-yl are each optionally substituted with oneor more groups selected from: chloro, cyano, ethoxy, fluoro, hydroxy,isopropoxy, methoxy, methyl, phenyl and trifluoromethyl.

In some embodiments, R³ is selected from: 2,3-difluorophenyl,2,4-difluorophenyl, 2,5-difluorophenyl, 2-chlorophenyl,2-fluoro-3-hydroxyphenyl, 2-fluoro-3-methoxyphenyl,2-fluoro-3-methylphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-methoxyphenyl, 2-methoxypyridin-4-yl, 3-(trifluoromethyl)phenyl,3,4-difluorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluoro-5-methylphenyl,3-fluorophenyl, 3-hydroxyphenyl, 3-isopropoxyphenyl, 3-methoxyphenyl,4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 5-cyano-2-fluorophenyl,5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylthiophen-2-yl,6-methoxypyridin-3-yl, benzhydryl, furan-2-yl, m-tolyl, phenyl, p-tolyl,thiophen-2-yl and thiophen-3-yl.

In some embodiments, R³ is 2,3-difluorophenyl.

In some embodiments, R³ is 2,4-difluorophenyl.

In some embodiments, R³ is 2,5-difluorophenyl.

In some embodiments, R³ is 2-chlorophenyl.

In some embodiments, R³ is 2-fluoro-3-hydroxyphenyl.

In some embodiments, R³ is 2-fluoro-3-methoxyphenyl.

In some embodiments, R³ is 2-fluoro-3-methylphenyl.

In some embodiments, R³ is 2-fluoro-4-methylphenyl.

In some embodiments, R³ is 2-fluorophenyl.

In some embodiments, R³ is 2-methoxyphenyl.

In some embodiments, R³ is 2-methoxypyridin-4-yl.

In some embodiments, R³ is 3-(trifluoromethyl)phenyl.

In some embodiments, R³ is 3,4-difluorophenyl.

In some embodiments, R³ is 3-chloro-2-fluorophenyl.

In some embodiments, R³ is 3-chloro-4-fluorophenyl.

In some embodiments, R³ is 3-chlorophenyl.

In some embodiments, R³ is 3-fluoro-5-methoxyphenyl.

In some embodiments, R³ is 3-fluoro-5-methylphenyl.

In some embodiments, R³ is 3-fluorophenyl.

In some embodiments, R³ is 3-hydroxyphenyl.

In some embodiments, R³ is 3-isopropoxyphenyl.

In some embodiments, R³ is 3-methoxyphenyl.

In some embodiments, R³ is 4-chlorophenyl.

In some embodiments, R³ is 4-fluorophenyl.

In some embodiments, R³ is 4-methoxyphenyl.

In some embodiments, R³ is 5-cyano-2-fluorophenyl.

In some embodiments, R³ is 5-fluoropyridin-3-yl.

In some embodiments, R³ is 5-methoxypyridin-3-yl.

In some embodiments, R³ is 5-methylthiophen-2-yl.

In some embodiments, R³ is 6-methoxypyridin-3-yl.

In some embodiments, R³ is benzhydryl, furan-2-yl.

In some embodiments, R³ is m-tolyl.

In some embodiments, R³ is phenyl.

In some embodiments, R³ is p-tolyl.

In some embodiments, R³ is thiophen-2-yl.

In some embodiments, R³ is thiophen-3-yl.

The Group R⁴:

In some embodiments, R⁴ is H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylthio, aryl and C₃-C₇ cycloalkyl; wherein said C₁-C₆ alkoxy, C₁-C₆alkyl, C₁-C₆ alkylthio, aryl and C₃-C₇ cycloalkyl are each optionallysubstituted with one or more groups selected from: C₁-C₆ alkoxy, C₁-C₆alkyl, carboxamide, cyano, halogen and hydroxy.

In some embodiments, R⁴ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl,C₁-C₆ alkylthio, aryl and C₃-C₇ cycloalkyl; wherein said C₁-C₆ alkoxy,C₁-C₆ alkyl, C₁-C₆ alkylthio, aryl and C₃-C₇ cycloalkyl are eachoptionally substituted with one or more groups selected from:carboxamide, chloro, cyano, ethoxy, fluoro, hydroxy, methoxy, methyl andtrifluoromethyl.

In some embodiments, R⁴ is selected from: H, butyl, cyclopropyl, ethyl,ethylthio, isopropyl, methoxy, methyl, methylthio, phenyl and propyl;wherein said butyl, cyclopropyl, ethyl, ethylthio, isopropyl, methoxy,methyl, methylthio, phenyl and propyl are each optionally substitutedwith one or more groups selected from: carboxamide, chloro, cyano,ethoxy, fluoro, hydroxy, methoxy, methyl and trifluoromethyl.

In some embodiments, R⁴ is selected from: H, 2,3-difluorophenyl,2,4-difluorophenyl, 2-amino-2-oxoethoxy, 2-cyanoethyl,2-ethoxyethylthio, 2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl,2-fluorophenyl, 2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-methoxyphenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl,4-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl,cyanomethylthio, cyclopropyl, ethyl, isopropyl, methyl, methylthio,m-tolyl, n-propyl, phenyl, p-tolyl and trifluoromethyl.

In some embodiments, R⁴ is selected from: H, 2,3-difluorophenyl,2,4-difluorophenyl, 2-amino-2-oxoethoxy, 2-cyanoethyl,2-ethoxyethylthio, 2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl,2-fluorophenyl, 2-hydroxyethyl, 2-hydroxyethylthio, 2-methoxyethyl,2-methoxyethylthio, 3,4-difluorophenyl, 3,4-dihydroxybutyl,3-chloro-2-fluorophenyl, 3-chlorophenyl, 3-fluoro-5-methoxyphenyl,3-fluorophenyl, 3-hydroxypropyl, 3-methoxyphenyl,4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, cyanomethylthio,cyclopropyl, ethyl, isopropyl, methyl, methylthio, m-tolyl, n-propyl,phenyl, p-tolyl and trifluoromethyl.

In some embodiments, R⁴ is H.

In some embodiments, R⁴ is 2,3-difluorophenyl.

In some embodiments, R⁴ is 2,4-difluorophenyl.

In some embodiments, R⁴ is 2-amino-2-oxoethoxy.

In some embodiments, R⁴ is 2-cyanoethyl.

In some embodiments, R⁴ is 2-ethoxyethylthio.

In some embodiments, R⁴ is 2-fluoro-4-methoxyphenyl.

In some embodiments, R⁴ is 2-fluoro-4-methylphenyl.

In some embodiments, R⁴ is 2-fluorophenyl.

In some embodiments, R⁴ is 2-hydroxyethyl.

In some embodiments, R⁴ is 2-hydroxyethylthio.

In some embodiments, R⁴ is 2-methoxyethyl.

In some embodiments, R⁴ is 2-methoxyethylthio.

In some embodiments, R⁴ is 3,4-difluorophenyl.

In some embodiments, R⁴ is 3,4-dihydroxybutyl.

In some embodiments, R⁴ is 3-chloro-2-fluorophenyl.

In some embodiments, R⁴ is 3-chlorophenyl.

In some embodiments, R⁴ is 3-fluoro-5-methoxyphenyl.

In some embodiments, R⁴ is 3-fluorophenyl.

In some embodiments, R⁴ is 3-hydroxypropyl.

In some embodiments, R⁴ is 3-methoxyphenyl.

In some embodiments, R⁴ is 4-chloro-2-fluorophenyl.

In some embodiments, R⁴ is 4-chloro-3-fluorophenyl.

In some embodiments, R⁴ is 4-chlorophenyl.

In some embodiments, R⁴ is 4-fluorophenyl.

In some embodiments, R⁴ is 4-hydroxyphenyl.

In some embodiments, R⁴ is 4-methoxyphenyl.

In some embodiments, R⁴ is cyanomethylthio.

In some embodiments, R⁴ is cyclopropyl.

In some embodiments, R⁴ is ethyl.

In some embodiments, R⁴ is isopropyl.

In some embodiments, R⁴ is methyl.

In some embodiments, R⁴ is methylthio.

In some embodiments, R⁴ is m-tolyl.

In some embodiments, R⁴ is n-propyl.

In some embodiments, R⁴ is phenyl.

In some embodiments, R⁴ is p-tolyl.

In some embodiments, R⁴ is trifluoromethyl.

Certain Combinations of the Present Invention:

In some embodiments, R², R³, and R⁴ are each independently selectedfrom: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylthio, aryl, C₃-C₇ cycloalkyl and heteroaryl;wherein said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylthio, aryl, C₃-C₇ cycloalkyl and heteroarylare each optionally substituted with one or more groups selected from:C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl,C₁-C₆ alkylthio, aryl, amino, carboxamide, cyano, C₁-C₆ haloalkyl,halogen and hydroxy.

In some embodiments, R², R³, and R⁴ are each independently selectedfrom: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylthio, aryl, C₃-C₇ cycloalkyl and heteroaryl;wherein said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylthio, aryl, C₃-C₇ cycloalkyl and heteroarylare each optionally substituted with one or more groups selected from:amino, carboxamide, chloro, cyano, ethoxy, fluoro, hydroxy, isopropoxy,methoxy, methyl, methylsulfinyl, methylsulfonyl, methylthio, phenyl andtrifluoromethyl.

In some embodiments, R², R³, and R⁴ are each independently selectedfrom: H, butyl, cyclopropyl, ethoxy, ethyl, ethylsulfinyl, ethylthio,furan-2-yl, isopropyl, methoxy, methyl, methylsulfinyl, methylsulfonyl,methylthio, phenyl, propyl, propylthio, pyridin-3-yl, pyridin-4-yl,thiophen-2-yl and thiophen-3-yl; wherein said butyl, cyclopropyl,ethoxy, ethyl, ethylsulfinyl, ethylthio, furan-2-yl, isopropyl, methoxy,methyl, methylsulfinyl, methylsulfonyl, methylthio, phenyl, propyl,propylthio, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl and thiophen-3-ylare each optionally substituted with one or more groups selected from:amino, carboxamide, chloro, cyano, ethoxy, fluoro, hydroxy, isopropoxy,methoxy, methyl, methylsulfinyl, methylsulfonyl, methylthio, phenyl andtrifluoromethyl.

In some embodiments, R², R³, and R⁴ are each independently selectedfrom: H, 2-(methylsulfinyl)ethyl, 2-(methylsulfonyl)ethyl,2-(methylthio)ethyl, 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2-aminoethylthio, 2-amino-2-oxoethoxy,2-chlorophenyl, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-3-hydroxyphenyl, 2-fluoro-3-methoxyphenyl,2-fluoro-3-methylphenyl, 2-fluoro-4-methoxyphenyl,2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-hydroxyethyl,2-hydroxyethylsulfinyl, 2-hydroxyethylthio, 2-methoxyethyl,2-methoxyethylthio, 2-methoxyphenyl, 2-methoxypyridin-4-yl,3-(trifluoromethyl)phenyl, 3,4-difluorophenyl, 3,4-dihydroxybutyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,3-fluoro-5-methoxyphenyl, 3-fluoro-5-methylphenyl, 3-fluorophenyl,3-hydroxyphenyl, 3-hydroxypropyl, 3-hydroxypropylthio,3-isopropoxyphenyl, 3-methoxyphenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-hydroxyphenyl, 4-methoxyphenyl, 5-cyano-2-fluorophenyl,5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylthiophen-2-yl,6-methoxypyridin-3-yl, benzhydryl, cyanomethoxy, cyanomethylthio,cyclopropyl, ethoxy, ethyl, ethylthio, furan-2-yl, isopropyl, methyl,methylsulfinyl, methylsulfonyl, methylthio, m-tolyl, n-propyl, phenyl,p-tolyl, thiophen-2-yl, thiophen-3-yl and trifluoromethyl.

In some embodiments, R² and R³ together with the pyrazole ring to whichthey are both attached to form a tricyclic heteroaryl.

In some embodiments, wherein R² and R³ together with the pyrazole ringto which they are both attached to form4,5-dihydro-3H-benzo[e]indazol-3-yl or indeno[2,1-c]pyrazol-1(8H)-yl.

In some embodiments, wherein R² and R³ together with the pyrazole ringto which they are both attached to form4,5-dihydro-3H-benzo[e]indazol-3-yl.

In some embodiments, wherein R² and R³ together with the pyrazole ringto which they are both attached to form indeno[2,1-c]pyrazol-1(8H)-yl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ic and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: H and C₁-C₆ alkyl;

R² is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl,C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, aryl and C₃-C₇ cycloalkyl; whereinsaid C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylthio, aryl and C₃-C₇ cycloalkyl are eachoptionally substituted with one or more groups selected from: C₁-C₆alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylthio, amino, carboxamide, cyano, halogen and hydroxy;

R³ is selected from: C₁-C₆ alkyl, aryl and heteroaryl; wherein saidC₁-C₆ alkyl, aryl and heteroaryl are each optionally substituted withone or more groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl,cyano, C₁-C₆ haloalkyl, halogen and hydroxy;

and

R⁴ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylthio, aryland C₃-C₇ cycloalkyl; wherein said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylthio, aryl and C₃-C₇ cycloalkyl are each optionally substitutedwith one or more groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,carboxamide, cyano, halogen and hydroxy.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ic and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: H and methyl;

R² is selected from: H, 2-(methylsulfinyl)ethyl,2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2,3-difluorophenyl,2-aminoethylthio, 2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 2-hydroxyethyl,2-hydroxyethylsulfinyl, 2-hydroxyethylthio, 2-methoxyethyl,2-methoxyethylthio, 3,4-difluorophenyl, 3,4-dihydroxybutyl,3-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-hydroxypropylthio, 3-methoxyphenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-methoxyphenyl, cyanomethoxy, cyanomethylthio, cyclopropyl, ethoxy,ethyl, ethylthio, isopropyl, methyl, methylsulfinyl, methylsulfonyl,methylthio, m-tolyl, n-propyl, phenyl and trifluoromethyl;

R³ is selected from: 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2-chlorophenyl, 2-fluoro-3-hydroxyphenyl,2-fluoro-3-methoxyphenyl, 2-fluoro-3-methylphenyl,2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,2-methoxypyridin-4-yl, 3-(trifluoromethyl)phenyl, 3,4-difluorophenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,3-fluoro-5-methoxyphenyl, 3-fluoro-5-methylphenyl, 3-fluorophenyl,3-hydroxyphenyl, 3-isopropoxyphenyl, 3-methoxyphenyl, 4-chlorophenyl,4-fluorophenyl, 4-methoxyphenyl, 5-cyano-2-fluorophenyl,5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylthiophen-2-yl,6-methoxypyridin-3-yl, benzhydryl, furan-2-yl, m-tolyl, phenyl, p-tolyl,thiophen-2-yl and thiophen-3-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-methoxyphenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl,4-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl,cyanomethylthio, cyclopropyl, ethyl, isopropyl, methyl, methylthio,m-tolyl, n-propyl, phenyl, p-tolyl and trifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ic and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: H and methyl;

R² is selected from: H, 2-(methylsulfinyl)ethyl,2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2,3-difluorophenyl,2-aminoethylthio, 2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 2-hydroxyethyl,2-hydroxyethylsulfinyl, 2-hydroxyethylthio, 2-methoxyethyl,2-methoxyethylthio, 3,4-difluorophenyl, 3,4-dihydroxybutyl,3-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-hydroxypropylthio, 3-methoxyphenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-methoxyphenyl, cyanomethoxy, cyanomethylthio, cyclopropyl, ethoxy,ethyl, ethylthio, isopropyl, methyl, methylsulfinyl, methylsulfonyl,methylthio, m-tolyl, n-propyl, phenyl, p-tolyl and trifluoromethyl;

R³ is selected from: 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2-chlorophenyl, 2-fluoro-3-hydroxyphenyl,2-fluoro-3-methoxyphenyl, 2-fluoro-3-methylphenyl,2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,2-methoxypyridin-4-yl, 3-(trifluoromethyl)phenyl, 3,4-difluorophenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,3-fluoro-5-methoxyphenyl, 3-fluoro-5-methylphenyl, 3-fluorophenyl,3-hydroxyphenyl, 3-isopropoxyphenyl, 3-methoxyphenyl, 4-chlorophenyl,4-fluorophenyl, 4-methoxyphenyl, 5-cyano-2-fluorophenyl,5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylthiophen-2-yl,6-methoxypyridin-3-yl, benzhydryl, furan-2-yl, m-tolyl, phenyl, p-tolyl,thiophen-2-yl and thiophen-3-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethyl, 2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-methoxyphenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-hydroxyphenyl, 4-methoxyphenyl, cyanomethylthio, cyclopropyl, ethyl,isopropyl, methyl, methylthio, m-tolyl, n-propyl, phenyl, p-tolyl andtrifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ic and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: H and C₁-C₆ alkyl;

R² and R³ together with the pyrazole ring to which they are bothattached to form a tricyclic heteroaryl;

and

R⁴ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylthio, aryland C₃-C₇ cycloalkyl; wherein said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylthio, aryl and C₃-C₇ cycloalkyl are each optionally substitutedwith one or more groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,carboxamide, cyano, halogen and hydroxy.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ic and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: H and methyl;

R² and R³ together with the pyrazole ring to which they are bothattached to form 4,5-dihydro-3H-benzo[e]indazol-3-yl orindeno[2,1-c]pyrazol-1 (8H)-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-methoxyphenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl,4-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl,cyanomethylthio, cyclopropyl, ethyl, isopropyl, methyl, methylthio,m-tolyl, n-propyl, phenyl, p-tolyl and trifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ic and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: H and methyl;

R² and R³ together with the pyrazole ring to which they are bothattached to form 4,5-dihydro-3H-benzo[e]indazol-3-yl orindeno[2,1-c]pyrazol-1 (8H)-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethyl, 2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-methoxyphenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-hydroxyphenyl, 4-methoxyphenyl, cyanomethylthio, cyclopropyl, ethyl,isopropyl, methyl, methylthio, m-tolyl, n-propyl, phenyl, p-tolyl andtrifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ie and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: H and C₁-C₆ alkyl;

R² is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl,C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, aryl and C₃-C₇ cycloalkyl; whereinsaid C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylthio, aryl and C₃-C₇ cycloalkyl are eachoptionally substituted with one or more groups selected from: C₁-C₆alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylthio, amino, carboxamide, cyano, halogen and hydroxy;

R³ is selected from: C₁-C₆ alkyl, aryl and heteroaryl; wherein saidC₁-C₆ alkyl, aryl and heteroaryl are each optionally substituted withone or more groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl,cyano, C₁-C₆ haloalkyl, halogen and hydroxy;

and

R⁴ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylthio, aryland C₃-C₇ cycloalkyl; wherein said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylthio, aryl and C₃-C₇ cycloalkyl are each optionally substitutedwith one or more groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,carboxamide, cyano, halogen and hydroxy.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ie and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: H and methyl;

R² is selected from: H, 2-(methylsulfinyl)ethyl,2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2,3-difluorophenyl,2-aminoethylthio, 2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 2-hydroxyethyl,2-hydroxyethylsulfinyl, 2-hydroxyethylthio, 2-methoxyethyl,2-methoxyethylthio, 3,4-difluorophenyl, 3,4-dihydroxybutyl,3-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-hydroxypropylthio, 3-methoxyphenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-methoxyphenyl, cyanomethoxy, cyanomethylthio, cyclopropyl, ethoxy,ethyl, ethylthio, isopropyl, methyl, methylsulfinyl, methylsulfonyl,methylthio, m-tolyl, n-propyl, phenyl and trifluoromethyl;

R³ is selected from: 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2-chlorophenyl, 2-fluoro-3-hydroxyphenyl,2-fluoro-3-methoxyphenyl, 2-fluoro-3-methylphenyl,2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,2-methoxypyridin-4-yl, 3-(trifluoromethyl)phenyl, 3,4-difluorophenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,3-fluoro-5-methoxyphenyl, 3-fluoro-5-methylphenyl, 3-fluorophenyl,3-hydroxyphenyl, 3-isopropoxyphenyl, 3-methoxyphenyl, 4-chlorophenyl,4-fluorophenyl, 4-methoxyphenyl, 5-cyano-2-fluorophenyl,5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylthiophen-2-yl,6-methoxypyridin-3-yl, benzhydryl, furan-2-yl, m-tolyl, phenyl, p-tolyl,thiophen-2-yl and thiophen-3-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-methoxyphenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl,4-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl,cyanomethylthio, cyclopropyl, ethyl, isopropyl, methyl, methylthio,m-tolyl, n-propyl, phenyl, p-tolyl and trifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ie and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: H and methyl;

R² is selected from: H, 2-(methylsulfinyl)ethyl,2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2,3-difluorophenyl,2-aminoethylthio, 2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 2-hydroxyethyl,2-hydroxyethylsulfinyl, 2-hydroxyethylthio, 2-methoxyethyl,2-methoxyethylthio, 3,4-difluorophenyl, 3,4-dihydroxybutyl,3-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-hydroxypropylthio, 3-methoxyphenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-methoxyphenyl, cyanomethoxy, cyanomethylthio, cyclopropyl, ethoxy,ethyl, ethylthio, isopropyl, methyl, methylsulfinyl, methylsulfonyl,methylthio, m-tolyl, n-propyl, phenyl, p-tolyl and trifluoromethyl;

R³ is selected from: 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2-chlorophenyl, 2-fluoro-3-hydroxyphenyl,2-fluoro-3-methoxyphenyl, 2-fluoro-3-methylphenyl,2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,2-methoxypyridin-4-yl, 3-(trifluoromethyl)phenyl, 3,4-difluorophenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,3-fluoro-5-methoxyphenyl, 3-fluoro-5-methylphenyl, 3-fluorophenyl,3-hydroxyphenyl, 3-isopropoxyphenyl, 3-methoxyphenyl, 4-chlorophenyl,4-fluorophenyl, 4-methoxyphenyl, 5-cyano-2-fluorophenyl,5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylthiophen-2-yl,6-methoxypyridin-3-yl, benzhydryl, furan-2-yl, m-tolyl, phenyl, p-tolyl,thiophen-2-yl and thiophen-3-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethyl, 2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-methoxyphenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-hydroxyphenyl, 4-methoxyphenyl, cyanomethylthio, cyclopropyl, ethyl,isopropyl, methyl, methylthio, m-tolyl, n-propyl, phenyl, p-tolyl andtrifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ie and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: H and C₁-C₆ alkyl;

R² and R³ together with the pyrazole ring to which they are bothattached to form a tricyclic heteroaryl;

and

R⁴ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylthio, aryland C₃-C₇ cycloalkyl; wherein said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylthio, aryl and C₃-C₇ cycloalkyl are each optionally substitutedwith one or more groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,carboxamide, cyano, halogen and hydroxy.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ie and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: H and methyl;

R² and R³ together with the pyrazole ring to which they are bothattached to form 4,5-dihydro-3H-benzo[e]indazol-3-yl orindeno[2,1-c]pyrazol-1(8H)-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-methoxyphenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl,4-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl,cyanomethylthio, cyclopropyl, ethyl, isopropyl, methyl, methylthio,m-tolyl, n-propyl, phenyl, p-tolyl and trifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ie and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: H and methyl;

R² and R³ together with the pyrazole ring to which they are bothattached to form 4,5-dihydro-3H-benzo[e]indazol-3-yl orindeno[2,1-c]pyrazol-1 (8H)-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethyl, 2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-methoxyphenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-hydroxyphenyl, 4-methoxyphenyl, cyanomethylthio, cyclopropyl, ethyl,isopropyl, methyl, methylthio, m-tolyl, n-propyl, phenyl, p-tolyl andtrifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ig and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl,C₁-C₅ alkylsulfonyl, C₁-C₆ alkylthio, aryl and C₃-C₇ cycloalkyl; whereinsaid C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ aikylthio, aryl and C₃-C₇ cycloalkyl are eachoptionally substituted with one or more groups selected from: C₁-C₆alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylthio, amino, carboxamide, cyano, halogen and hydroxy;

R³ is selected from: C₁-C₆ alkyl, aryl and heteroaryl; wherein saidC₁-C₆ alkyl, aryl and heteroaryl are each optionally substituted withone or more groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl,cyano, C₁-C₆ haloalkyl, halogen and hydroxy;

and

R⁴ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylthio, aryland C₃-C₇ cycloalkyl; wherein said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylthio, aryl and C₃-C₇ cycloalkyl are each optionally substitutedwith one or more groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,carboxamide, cyano, halogen and hydroxy.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ig and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: H, 2-(methylsulfinyl)ethyl,2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2,3-difluorophenyl,2-aminoethylthio, 2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 2-hydroxyethyl,2-hydroxyethylsulfinyl, 2-hydroxyethylthio, 2-methoxyethyl,2-methoxyethylthio, 3,4-difluorophenyl, 3,4-dihydroxybutyl,3-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-hydroxypropylthio, 3-methoxyphenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-methoxyphenyl, cyanomethoxy, cyanomethylthio, cyclopropyl, ethoxy,ethyl, ethylthio, isopropyl, methyl, methylsulfinyl, methylsulfonyl,methylthio, m-tolyl, n-propyl, phenyl and trifluoromethyl; R³ isselected from: 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2-chlorophenyl, 2-fluoro-3-hydroxyphenyl,2-fluoro-3-methoxyphenyl, 2-fluoro-3-methylphenyl,2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,2-methoxypyridin-4-yl, 3-(trifluoromethyl)phenyl, 3,4-difluorophenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,3-fluoro-5-methoxyphenyl, 3-fluoro-5-methylphenyl, 3-fluorophenyl,3-hydroxyphenyl, 3-isopropoxyphenyl, 3-methoxyphenyl, 4-chlorophenyl,4-fluorophenyl, 4-methoxyphenyl, 5-cyano-2-fluorophenyl,5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylthiophen-2-yl,6-methoxypyridin-3-yl, benzhydryl, furan-2-yl, m-tolyl, phenyl, p-tolyl,thiophen-2-yl and thiophen-3-yl;

-   -   and R⁴ is selected from: H, 2,3-difluorophenyl,        2,4-difluorophenyl, 2-amino-2-oxoethoxy, 2-cyanoethyl,        2-ethoxyethylthio, 2-fluoro-4-methoxyphenyl,        2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-hydroxyethylthio,        2-methoxyethyl, 2-methoxyethylthio, 3,4-difluorophenyl,        3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl, 3-chlorophenyl,        3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,        4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl,        4-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl,        4-methoxyphenyl, cyanomethylthio, cyclopropyl, ethyl, isopropyl,        methyl, methylthio, m-tolyl, n-propyl, phenyl, p-tolyl and        trifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ig and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: H, 2-(methylsulfinyl)ethyl,2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2,3-difluorophenyl,2-aminoethylthio, 2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 2-hydroxyethyl,2-hydroxyethylsulfinyl, 2-hydroxyethylthio, 2-methoxyethyl,2-methoxyethylthio, 3,4-difluorophenyl, 3,4-dihydroxybutyl,3-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-hydroxypropylthio, 3-methoxyphenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-methoxyphenyl, cyanomethoxy, cyanomethylthio, cyclopropyl, ethoxy,ethyl, ethylthio, isopropyl, methyl, methylsulfinyl, methylsulfonyl,methylthio, m-tolyl, n-propyl, phenyl, p-tolyl and trifluoromethyl; R³is selected from: 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2-chlorophenyl, 2-fluoro-3-hydroxyphenyl,2-fluoro-3-methoxyphenyl, 2-fluoro-3-methylphenyl,2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,2-methoxypyridin-4-yl, 3-(trifluoromethyl)phenyl, 3,4-difluorophenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,3-fluoro-5-methoxyphenyl, 3-fluoro-5-methylphenyl, 3-fluorophenyl,3-hydroxyphenyl, 3-isopropoxyphenyl, 3-methoxyphenyl, 4-chlorophenyl,4-fluorophenyl, 4-methoxyphenyl, 5-cyano-2-fluorophenyl,5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylthiophen-2-yl,6-methoxypyridin-3-yl, benzhydryl, furan-2-yl, m-tolyl, phenyl, p-tolyl,thiophen-2-yl and thiophen-3-yl;

-   -   and R⁴ is selected from: H, 2,3-difluorophenyl,        2,4-difluorophenyl, 2-amino-2-oxoethoxy, 2-cyanoethyl,        2-ethoxyethylthio, 2-fluoro-4-methoxyphenyl,        2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-hydroxyethyl,        2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,        3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,        3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,        3-hydroxypropyl, 3-methoxyphenyl, 4-chloro-2-fluorophenyl,        4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,        4-hydroxyphenyl, 4-methoxyphenyl, cyanomethylthio, cyclopropyl,        ethyl, isopropyl, methyl, methylthio, m-tolyl, n-propyl, phenyl,        p-tolyl and trifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ig and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² and R³ together with the pyrazole ring to which they are bothattached to form a tricyclic heteroaryl;

and

R⁴ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylthio, aryland C₃-C₇ cycloalkyl; wherein said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylthio, aryl and C₃-C₇ cycloalkyl are each optionally substitutedwith one or more groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,carboxamide, cyano, halogen and hydroxy.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ig and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² and R³ together with the pyrazole ring to which they are bothattached to form 4,5-dihydro-3H-benzo[e]indazol-3-yl orindeno[2,1-c]pyrazol-1(8H)-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-methoxyphenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl,4-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl,cyanomethylthio, cyclopropyl, ethyl, isopropyl, methyl, methylthio,m-tolyl, n-propyl, phenyl, p-tolyl and trifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ig and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² and R³ together with the pyrazole ring to which they are bothattached to form 4,5-dihydro-3H-benzo[e]indazol-3-yl orindeno[2,1-c]pyrazol-1(8H)-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethyl, 2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-methoxyphenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-hydroxyphenyl, 4-methoxyphenyl, cyanomethylthio, cyclopropyl, ethyl,isopropyl, methyl, methylthio, m-tolyl, n-propyl, phenyl, p-tolyl andtrifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ii and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl,C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, aryl and C₃-C₇ cycloalkyl; whereinsaid C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylthio, aryl and C₃-C₇ cycloalkyl are eachoptionally substituted with one or more groups selected from: C₁-C₆alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylthio, amino, carboxamide, cyano, halogen and hydroxy;

R³ is selected from: C₁-C₆ alkyl, aryl and heteroaryl; wherein saidC₁-C₆ alkyl, aryl and heteroaryl are each optionally substituted withone or more groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl,cyano, C₁-C₆ haloalkyl, halogen and hydroxy;

and

R⁴ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylthio, aryland C₃-C₇ cycloalkyl; wherein said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylthio, aryl and C₃-C₇ cycloalkyl are each optionally substitutedwith one or more groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,carboxamide, cyano, halogen and hydroxy.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ii and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: H, 2-(methylsulfinyl)ethyl,2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2,3-difluorophenyl,2-aminoethylthio, 2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 2-hydroxyethyl,2-hydroxyethylsulfinyl, 2-hydroxyethylthio, 2-methoxyethyl,2-methoxyethylthio, 3,4-difluorophenyl, 3,4-dihydroxybutyl,3-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-hydroxypropylthio, 3-methoxyphenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-methoxyphenyl, cyanomethoxy, cyanomethylthio, cyclopropyl, ethoxy,ethyl, ethylthio, isopropyl, methyl, methylsulfinyl, methylsulfonyl,methylthio, m-tolyl, n-propyl, phenyl and trifluoromethyl;

R³ is selected from: 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2-chlorophenyl, 2-fluoro-3-hydroxyphenyl,2-fluoro-3-methoxyphenyl, 2-fluoro-3-methylphenyl,2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,2-methoxypyridin-4-yl, 3-(trifluoromethyl)phenyl, 3,4-difluorophenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,3-fluoro-5-methoxyphenyl, 3-fluoro-5-methylphenyl, 3-fluorophenyl,3-hydroxyphenyl, 3-isopropoxyphenyl, 3-methoxyphenyl, 4-chlorophenyl,4-fluorophenyl, 4-methoxyphenyl, 5-cyano-2-fluorophenyl,5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylthiophen-2-yl,6-methoxypyridin-3-yl, benzhydryl, furan-2-yl, m-tolyl, phenyl, p-tolyl,thiophen-2-yl and thiophen-3-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-methoxyphenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl,4-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl,cyanomethylthio, cyclopropyl, ethyl, isopropyl, methyl, methylthio,m-tolyl, n-propyl, phenyl, p-tolyl and trifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ii and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: H, 2-(methylsulfinyl)ethyl,2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2,3-difluorophenyl,2-aminoethylthio, 2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 2-hydroxyethyl,2-hydroxyethylsulfinyl, 2-hydroxyethylthio, 2-methoxyethyl,2-methoxyethylthio, 3,4-difluorophenyl, 3,4-dihydroxybutyl,3-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-hydroxypropylthio, 3-methoxyphenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-methoxyphenyl, cyanomethoxy, cyanomethylthio, cyclopropyl, ethoxy,ethyl, ethylthio, isopropyl, methyl, methylsulfinyl, methylsulfonyl,methylthio, m-tolyl, n-propyl, phenyl, p-tolyl and trifluoromethyl;

R³ is selected from: 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2-chlorophenyl, 2-fluoro-3-hydroxyphenyl,2-fluoro-3-methoxyphenyl, 2-fluoro-3-methylphenyl,2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,2-methoxypyridin-4-yl, 3-(trifluoromethyl)phenyl, 3,4-difluorophenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,3-fluoro-5-methoxyphenyl, 3-fluoro-5-methylphenyl, 3-fluorophenyl,3-hydroxyphenyl, 3-isopropoxyphenyl, 3-methoxyphenyl, 4-chlorophenyl,4-fluorophenyl, 4-methoxyphenyl, 5-cyano-2-fluorophenyl,5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylthiophen-2-yl,6-methoxypyridin-3-yl, benzhydryl, furan-2-yl, m-tolyl, phenyl, p-tolyl,thiophen-2-yl and thiophen-3-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethyl, 2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-methoxyphenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-hydroxyphenyl, 4-methoxyphenyl, cyanomethylthio, cyclopropyl, ethyl,isopropyl, methyl, methylthio, m-tolyl, n-propyl, phenyl, p-tolyl andtrifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ii and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² and R³ together with the pyrazole ring to which they are bothattached to form a tricyclic heteroaryl;

and

R⁴ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylthio, aryland C₃-C₇ cycloalkyl; wherein said C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylthio, aryl and C₃-C₇ cycloalkyl are each optionally substitutedwith one or more groups selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,carboxamide, cyano, halogen and hydroxy.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ii and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² and R³ together with the pyrazole ring to which they are bothattached to form 4,5-dihydro-3H-benzo[e]indazol-3-yl orindeno[2,1-c]pyrazol-1(8H)-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-methoxyphenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl,4-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl,cyanomethylthio, cyclopropyl, ethyl, isopropyl, methyl, methylthio,m-tolyl, n-propyl, phenyl, p-tolyl and trifluoromethyl.

One aspect of the present invention encompasses certain pyrazolederivatives selected from compounds of Formula Ii and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² and R³ together with the pyrazole ring to which they are bothattached to form 4,5-dihydro-3H-benzo[e]indazol-3-yl orindeno[2,1-c]pyrazol-1(8H)-yl;

and

R⁴ is selected from: H, 2,3-difluorophenyl, 2,4-difluorophenyl,2-amino-2-oxoethoxy, 2-cyanoethyl, 2-ethoxyethylthio,2-fluoro-4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-hydroxyethyl, 2-hydroxyethylthio, 2-methoxyethyl, 2-methoxyethylthio,3,4-difluorophenyl, 3,4-dihydroxybutyl, 3-chloro-2-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-hydroxypropyl, 3-methoxyphenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-hydroxyphenyl, 4-methoxyphenyl, cyanomethylthio, cyclopropyl, ethyl,isopropyl, methyl, methylthio, m-tolyl, n-propyl, phenyl, p-tolyl andtrifluoromethyl.

Some embodiments of the present invention include every combination ofone or more compounds selected from the following group shown in TABLEA.

TABLE A Cpd No. Chemical Structure Chemical Name 1

2-(((1r,4r)-4-((5-(4- fluorophenyl)-3- (methylthio)-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 2

2-(((1r,4r)-4-((3-(4- fluorophenyl)-5- (methylthio)-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 3

2-(((1s,4s)-4-((3,4- diphenyl-1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 4

2-(((1r,4r)-4-((1-phenyl- 4,5-dihydro-3H- benzo[e]indazol-3-yl)methyl)cyclohexyl) methoxy)acetic acid 5

2-(((1r,4r)-4-((3- phenylindeno[2,1- c]pyrazol-1(8H)-yl)methyl)cyclohexyl) methoxy)acetic acid 6

2-(((1r,4r)-4-((4-(3- methoxyphenyl)-3-methyl- 5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 7

2-(((1r,4r)-4-((4-(3- methoxyphenyl)-5-methyl- 3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 8

2-(((1r,4r)-4-((3,4- diphenyl-1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 9

2-(((1r,4r)-4-((4,5- diphenyl-1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 10

2-(((1s,4s)-4-((3-(4- fluorophenyl)-5- (methylthio)-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 11

2-(((1r,4r)-4-((5-methyl- 3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 12

2-(((1s,4s)-4-((5-(4- fluorophenyl)-3- (methylthio)-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 13

2-(((1s,4s)-4-((4-(3- methoxyphenyl)-3-methyl- 5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 14

2-(((1s,4s)-4-((4-(3- methoxyphenyl)-5-methyl- 3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 15

2-(((1s,4s)-4-((3-methyl- 4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 16

2-(((1s,4s)-4-((5-methyl- 3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 17

2-(((1s,4s)-4-((4- benzhydryl-1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 18

2-(((1r,4r)-4-((4- benzhydryl-1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 19

2-(((1s,4s)-4-((3-methyl-5- phenyl-4-m-tolyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 20

2-(((1s,4s)-4-((4-(2,5- difluorophenyl)-5-methyl- 3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 21

2-(((1s,4s)-4-((4-(4- chlorophenyl)-3-methyl-5- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 22

2-(((1s,4s)-4-((4-(4- fluorophenyl)-5-methyl-3- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 23

2-(((1s,4s)-4-((4-(3- chlorophenyl)-5-methyl-3- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 24

2-(((1s,4s)-4-((5-methyl-3- phenyl-4-m-tolyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 25

2-(((1s,4s)-4-((4-(4- fluorophenyl)-3-methyl-5- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 26

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-3-methyl- 5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 27

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-5-methyl- 3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 28

2-(((1s,4s)-4-((4-(4- chlorophenyl)-5-methyl-3- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 29

2-(((1s,4s)-4-((4-(2,5- difluorophenyl)-3-methyl- 5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 30

2-(((1s,4s)-4-((4-(3- methoxyphenyl)-3- (methylthio)-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 31

2-(((1s,4s)-4-((4-(3- methoxyphenyl)-5- (methylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 32

2-(((1s,4s)-4-((5-(3- methoxyphenyl)-3-methyl- 4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 33

2-(((1s,4s)-4-((3-(3- methoxyphenyl)-5-methyl- 4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 34

2-(((1s,4s)-4-((5-(3-fluoro- 5-methoxyphenyl)-3- methyl-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 35

2-(((1s,4s)-4-((3-(3-fluoro- 5-methoxyphenyl)-5- methyl-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 36

2-(((1s,4s)-4-((5-(4- methoxyphenyl)-3- (methylthio)-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 37

2-(((1s,4s)-4-((3-(4- methoxyphenyl)-5- (methylthio)-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 38

2-(((1s,4s)-4-((4-(4- methoxyphenyl)-5-methyl- 3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 39

2-(((1s,4s)-4-((4-(3-fluoro- 5-methoxyphenyl)-5- methyl-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 40

2-(((1s,4s)-4-((4-(3- fluorophenyl)-5-methyl-3- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 41

2-(((1s,4s)-4-((4-(3- chlorophenyl)-3-methyl-5- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 42

2-(((1s,4s)-4-((4-(3- methoxyphenyl)-3-methyl- 5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 43

2-(((1s,4s)-4-((4-(3-fluoro- 5-methoxyphenyl)-3- methyl-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 44

2-(((1s,4s)-4-((4-(2- chlorophenyl)-5-methyl-3- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 45

2-(((1s,4s)-4-((4-(2- chlorophenyl)-3-methyl-5- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 46

2-(((1s,4s)-4-((4-(3- fluorophenyl)-3-methyl-5- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 47

2-(((1s,4s)-4-((5-methyl-3- phenyl-4-p-tolyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 48

2-(((1s,4s)-4-((4-(2,4- difluorophenyl)-5-methyl- 3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 49

2-(((1s,4s)-4-((4-(4- chlorophenyl)-3-phenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 50

2-(((1s,4s)-4-((4-(3- fluorophenyl)-3-phenyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 51

2-(((1s,4s)-4-((4-(4- fluorophenyl)-3-phenyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 52

2-(((1s,4s)-4-((4-(3-chloro- 2-fluorophenyl)-5-methyl-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 53

2-(((1s,4s)-4-((4-(2,4- difluorophenyl)-3-methyl- 5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 54

2-(((1s,4s)-4-((4-(3-chloro- 2-fluorophenyl)-3-methyl-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 55

2-(((1s,4s)-4-((3-methyl-5- phenyl-4-p-tolyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 56

2-(((1s,4s)-4-((4-(3-chloro- 4-fluorophenyl)-3-methyl-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 57

2-(((1s,4s)-4-((4-(3-chloro- 4-fluorophenyl)-5-methyl-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 58

2-(((1s,4s)-4-((4-(4- methoxyphenyl)-3-phenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 59

2-(((1s,4s)-4-((4-(2- methoxyphenyl)-3-phenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 60

2-(((1s,4s)-4-((3-phenyl-4- m-tolyl-1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 61

2-((1s,4s)-4-((3-phenyl-4- p-tolyl-1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 62

2-(((1s,4s)-4-((4-(3- chlorophenyl)-3-phenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 63

2-(((1s,4s)-4-((4-(2- fluorophenyl)-3-phenyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 64

2-(((1s,4s)-4-((3-methyl-4- phenyl-5-m-tolyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 65

2-(((1s,4s)-4-((5-methyl-4- phenyl-3-m-tolyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 66

2-(((1s,4s)-4-((3-(3- chlorophenyl)-5-methyl-4- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 67

2-(((1s,4s)-4-((5-(3- fluorophenyl)-3-methyl-4- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 68

2-(((1s,4s)-4-((3-(3- fluorophenyl)-5-methyl-4- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 69

2-(((1s,4s)-4-((5-(3-chloro- 2-fluorophenyl)-3-methyl-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 70

2-(((1s,4s)-4-((3-(3-chloro- 2-fluorophenyl)-5-methyl-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 71

2-(((1s,4s)-4-((5-(2- fluorophenyl)-3-methyl-4- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 72

2-(((1s,4s)-4-((3-(2- fluorophenyl)-5-methyl-4- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 73

2-(((1s,4s)-4-((5-(2,3- difluorophenyl)-3-methyl- 4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 74

2-(((1s,4s)-4-((3-(2,3- difluorophenyl)-5-methyl- 4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 75

2-(((1s,4s)-4-((3- (methylthio)-4,5-diphenyl- 1H-pyrazol-1-yl)methyl)cycloheicyl) methoxy)acetic acid 76

2-(((1s,4s)-4-((5- (methylthio)-3,4-diphenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 77

2-(((1s,4s)-4-((4-(2,5- difluorophenyl)-3- (methylthio)-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 78

2-(((1s,4s)-4-((4-(2,5- difluorophenyl)-5- (methylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 79

2-(((1s,4s)-4-((4-(5-cyano- 2-fluorophenyl)-5- (methylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 80

2-(((1s,4s)-4-((4-(3,4- difluorophenyl)-5-ethoxy- 3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 81

2-(((1s,4s)-4-((5-ethoxy- 3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 82

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-3- (methylthio)-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 83

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-5- (methylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 84

2-(((1s,4s)-4-((4-(3- isopropoxyphenyl)-3- (methylthio)-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 85

2-(((1s,4s)-4-((4-(3- isopropoxyphenyl)-5- (methylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 86

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-5- (methylsulfonyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 87

2-(((1s,4s)-4-((4-(2,5- difluorophenyl)-5- (methylsulfonyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 88

2-(((1s,4s)-4-((5- (ethylthio)-3,4-diphenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 89

2-(((1s,4s)-4-((5- (ethylthio)-4-(3- methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 90

2-(((1s,4s)-4-((5- (ethylthio)-4-(2-fluoro-3- methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 91

2-(((1s,4s)-4-((4-(3- fluorophenyl)-5- (methylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 92

2-(((1s,4s)-4-((4-(2-fluoro- 3-methoxyphenyl)-5-(methylthio)-3-phenyl-1H- pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 93

2-(((1s,4s)-4-((4-(3-fluoro- 5-methoxyphenyl)-5-(methylthio)-3-phenyl-1H- pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 94

2-(((1s,4s)-4-((4-(4- fluorophenyl)-5- (methylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 95

2-(((1s,4s)-4-((4-(3- chlorophenyl)-5- (methylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 96

2-(((1s,4s)-4-((5- (methylthio)-3-phenyl-4-(3- (trifluoromethyl)phenyl)-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 97

2-(((1s,4s)-4-((4-(4- chlorophenyl)-5- (methylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 98

2-(((1s,4s)-4-((3-ethyl-4-(3- methoxyphenyl)-5-phenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 99

2-(((1s,4s)-4-((5-ethyl-4-(3- methoxyphenyl)-3-phenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 100

2-(((1s,4s)-4-((3-ethyl-4,5- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 101

2-(((1s,4s)-4-((5-ethyl-3,4- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 102

2-(((1s,4s)-4-((3-ethyl-4-(3- fluorophenyl)-5-phenyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 103

2-(((1s,4s)-4-((5-ethyl-4-(3- fluorophenyl)-3-phenyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 104

2-(((1s,4s)-4-((3-ethyl-4-(2- fluoro-3-methoxyphenyl)-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 105

2-(((1s,4s)-4-((5-ethyl-4-(2- fluoro-3-methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 106

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-3-ethyl-5- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 107

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-5-ethyl-3- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 108

2-(((1s,4s)-4-((5- (methylthio)-3-phenyl-4- (thiophen-2-yl)-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 109

2-(((1s,4s)-4-((4-(furan-2- yl)-5-(methylthio)-3- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 110

2-(((1s,4s)-4-((5- (methylthio)-3-phenyl-4- (thiophen-3-yl)-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 111

2-(((1s,4s)-4-((5- (methylthio)-4-(5- methylthiophen-2-yl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 112

2-(((1s,4s)-4-((3-isopropyl- 4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 113

2-(((1s,4s)-4-((4-(3- fluorophenyl)-5-isopropyl- 3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 114

2-(((1s,4s)-4-((4-(3- methoxyphenyl)-5- (methylsulfinyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 115

2-(((1s,4s)-4-((4-(3- chlorophenyl)-3-ethyl-5- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 116

2-(((1s,4s)-4-((4-(3- chlorophenyl)-5-ethyl-3- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 117

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-5- isopropyl-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 118

2-(((1s,4s)-4-((5- (ethylthio)-4-(2- fluorophenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 119

2-(((1s,4s)-4-((5- (ethylthio)-4-(3-fluoro-5- methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 120

2-(((1s,4s)-4-((5- cyclopropyl-4-(3- methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 121

2-(((1s,4s)-4-((3- cyclopropyl-4,5-diphenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 122

2-(((1s,4s)-4-((5- cyclopropyl-3,4-diphenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 123

2-(((1s,4s)-4-((3-isopropyl- 4-(3-methoxyphenyl)-5- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 124

2-(((1s,4s)-4-((4-(3 chlorophenyl)-3-isopropyl- 5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 125

2-(((1s,4s)-4-((4-(2-fluoro- 3-methoxyphenyl)-3- isopropyl-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 126

2-(((1s,4s)-4-((5- cyclopropyl-4-(2-fluoro-3- methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 127

2-(((1s,4s)-4-((5- cyclopropyl-4-(2,3- difluorophenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 128

2-(((1s,4s)-4-((5-isopropyl- 4-(3-methoxyphenyl)-3- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 129

2-(((1s,4s)-4-((4-(3- chlorophenyl)-5-isopropyl- 3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 130

2-(((1s,4s)-4-((4-(2-fluoro- 3-methoxyphenyl)-5- isopropyl-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 131

methyl 2-(((1s,4s)-4-((5- (methylthio)-3,4-diphenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetate 132

2-(((1s,4s)-4-((4-(3- chlorophenyl)-3- cyclopropyl-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 133

2-(((1s,4s)-4-((4-(3- chlorophenyl)-5- cyclopropyl-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 134

2-(((1s,4s)-4-((4-(3-fluoro- 5-methylphenyl)-5-(methylthio)-3-phenyl-1H- pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 135

2-(((1s,4s)-4-((4-(5- fluoropyridin-3-yl)-5- (methylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 136

methyl 2-(((1s,4s)-4-((4-(3- methoxyphenyl)-5-methyl-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetate 137

2-(((1s,4s)-4-((3-(4- fluorophenyl)-5-methyl-4- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 138

2-(((1s,4s)-4-((3-(4- chlorophenyl)-5-methyl-4- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 139

2-(((1s,4s)-4-((5-methyl-4- phenyl-3-p-tolyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 140

2-(((1s,4s)-4-((3-(4- methoxyphenyl)-5-methyl- 4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 141

2-(((1s,4s)-4-((3-(2,4- difluorophenyl)-5-methyl- 4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 142

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-5- (ethylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 143

2-(((1s,4s)-4-((3-(2-fluoro- 4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 144

2-(((1s,4s)-4-((3-(4-chloro- 2-fluorophenyl)-5-methyl-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 145

2-(((1s,4s)-4-((3-(2-fluoro- 4-methoxyphenyl)-5- methyl-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 146

2-(((1s,4s)-4-((5-(2- hydroxyethylthio)-3,4- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 147

2-(((1s,4s)-4-((4-(5- fluoropyridin-3-yl)-5- methyl-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 148

2-(((1s,4s)-4-((5- (ethylthio)-4-(5- fluoropyridin-3-yl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 149

2-(((1s,4s)-4-((5-ethyl-4-(5- fluoropyridin-3-yl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 150

2-(((1s,4s)-4-((1-phenyl- 4,5-dihydro-3H- benzo[e]indazol-3-yl)methyl)cyclohexyl) methoxy)acetic acid 151

2-(((1s,4s)-4-((3,4- diphenyl-5- (trifluoromethyl)-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 152

2-(((1s,4s)-4-((3-phenyl-4- p-tolyl-5-(trifluoromethyl)- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 153

2-(((1s,4s)-4-((4-(3- hydroxyphenyl)-5-methyl- 3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 154

2-(((1s,4s)-4-((4-(3- methoxyphenyl)-5-phenyl- 3-(trifluoromethyl)-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 155

2-(((1s,4s)-4-((4-(3- methoxyphenyl)-3-phenyl- 5-(trifluoromethyl)-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 156

2-(((1R,4s)-4-((3-((S)-3,4- dihydroxybutyl)-4,5- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 157

2-(((1R,4s)-4-((5-((S)-3,4- dihydroxybutyl)-3,4- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 158

2-(((1R,4s)-4-((5-((S)-3,4- dihydroxybutyl)-4-(3-fluorophenyl)-3-phenyl-1H- pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 159

2-(((1R,4s)-4-((4-(3,4- difluorophenyl)-3-((S)-3,4-dihydroxybutyl)-5-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 160

2-(((1R,4s)-4-((4-(3,4- difluorophenyl)-5-((S)-3,4-dihydroxybutyl)-3-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 161

2-(((1R,4s)-4-((5-((S)-3,4- dihydroxybutyl)-4-(3-hydroxyphenyl)-3-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 162

2-(((1R,4s)-4-((4-(3- chlorophenyl)-5-((S)-3,4-dihydroxybutyl)-3-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 163

2-(((1s,4s)-4-((3-(4- chlorophenyl)-5-ethyl-4- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 164

2-(((1s,4s)-4-((5-ethyl-3-(4- fluorophenyl)-4-phenyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 165

2-(((1s,4s)-4-((5-ethyl-3-(2- fluoro-4-methoxyphenyl)-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 166

2-(((1s,4s)-4-((5-ethyl-3-(4- methoxyphenyl)-4-phenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 167

2-(((1s,4s)-4-((5-ethyl-3-(2- fluoro-4-methylphenyl)-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 168

2-(((1s,4s)-4-((5-ethyl-4- phenyl-3-p-tolyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 169

2-(((1S,4s)-4-((5-((R)-3,4- dihydroxybutyl)-4-(3-fluorophenyl)-3-phenyl-1H- pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 170

2-(((1S,4s)-4-((4-(3,4- difluorophenyl)-5-((R)-3,4-dihydroxybutyl)-3-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 171

2-(((1S,4s)-4-((4-(3- chlorophenyl)-5-(R)-3,4- dihydroxybutyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 172

2-(((1s,4s)-4-((5-ethyl-4-(3- hydroxyphenyl)-3-phenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 173

2-(((1s,4s)-4-((4-(3- hydroxyphenyl)-5- (methylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 174

2-(((1s,4s)-4-((5- (ethylthio)-4-(2-fluoro-3- hydroxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 175

2-(((1s,4s)-4-((5-ethyl-3-(4- hydroxyphenyl)-4-phenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 176

2-(((1s,4s)-4-((3-(4-chloro- 3-fluorophenyl)-5-ethyl-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 177

2-(((1s,4s)-4-((5- (ethylthio)-4-(3- hydroxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 178

2-(((1s,4s)-4-((5-(2- methoxyethyl)-3,4- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 179

2-(((1s,4s)-4-((5-(2- methoxyethyl)-4-(3- methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 180

2-(((1s,4s)-4-((4-(3- hydroxyphenyl)-5-(2- methoxyethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 181

2-(((1s,4s)-4-((5-(2- methoxyethyl)-4-(6- methoxypyridin-3-yl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 182

2-(((1s,4s)-4-((4-(2-fluoro- 3-hydroxyphenyl)-5-(2-methoxyethyl)-3-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 183

2-(((1s,4s)-4-((3- (cyanomethylthio)-4,5- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 184

2-(((1s,4s)-4-((5- (cyanomethylthio)-3,4- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 185

2-(((1s,4s)-4-((3-(2- ethoxyethylthio)4,5- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 186

2-(((1s,4s)-4-((5-(2- ethoxyethylthio)-3,4- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 187

2-(((1s,4s)-4-((5-(3- hydroxypropylthio)-3,4- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 188

2-(((1s,4s)-4-((3-(2- methoxyethylthio)-4,5- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 189

2-(((1s,4s)-4-((5-(2- methoxyethylthio)-3,4- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 190

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-5-(2- methoxyethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 191

2-(((1s,4s)-4-((4-(3-chloro- 2-fluorophenyl)-5-(2-methoxyethyl)-3-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 192

2-(((1s,4s)-4-((4-(2-fluoro- 3-methylphenyl)-5-(2-methoxyethyl)-3-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 193

2-(((1s,4s)-4-((5-(2- methoxyethyl)-3-phenyl-4- m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 194

2-(((1s,4s)-4-((4-(3- fluorophenyl)-5-(2- methoxyethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 195

2-(((1s,4s)-4-((4-(2- methoxypyridin-4-yl)-5- methyl-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 196

2-(((1s,4s)-4-((5-ethyl-4-(2- methoxypyridin-4-yl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 197

2-(((1s,4s)-4-((4-(3- chlorophenyl)-5-(2- methoxyethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 198

2-(((1s,4s)-4-((5-(2- hydroxyethylthio)-4-(3- methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 199

2-(((1s,4s)-4-((4-(3- chlorophenyl)-5-(2- hydroxyethylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 200

2-(((1s,4s)-4-((5-(2- hydroxyethylthio)-4- phenyl-3-p-tolyl-1H-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 201

2-(((1s,4s)-4-((5-ethyl-4-(5- methoxypyridin-3-yl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 202

2-(((1s,4s)-4-((4-(3- methoxyphenyl)-3-phenyl- 5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 203

2-(((1s,4s)-4-((4-(3- fluorophenyl)-3-phenyl-5- propyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 204

2-(((1s,4s)-4-((4-(3- chlorophenyl)-3-phenyl-5- propyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 205

2-(((1s,4s)-4-((3-phenyl-5- propyl-4-m-tolyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 206

2-(((1s,4s)-4-((4-(2-fluoro- 3-methoxyphenyl)-3- phenyl-5-propyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 207

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-3-phenyl- 5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 208

2-(((1s,4s)-4-((4-(3-chloro- 2-fluorophenyl)-3-phenyl-5-propyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 209

2-(((1s,4s)-4-((4-(2-fluoro- 3-methylphenyl)-3-phenyl-5-propyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 210

2-(((1s,4s)-4-((5-(2- hydroxyethylthio)-3- phenyl-4-m-tolyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 211

2-(((1s,4s)-4-((4-(2-fluoro- 3-hydroxyphenyl)-3- phenyl-5-propyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 212

2-(((1s,4s)-4-((4-(3- fluorophenyl)-5-(2- hydroxyethylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 213

2-(((1s,4s)-4-((4-(2-fluoro- 3-hydroxyphenyl)-5-(2-(methylthio)ethyl)-3- phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 214

2-(((1s,4s)-4-((4-(5- methoxypyridin-3-yl)-5- methyl-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 215

2-(((1s,4s)-4-((4-(3-chloro- 2-fluorophenyl)-5-(2- (methylthio)ethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 216

2-(((1s,4s)-4-((5-(2- (methylthio)ethyl)-3- phenyl-4-m-tolyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 217

2-(((1s,4s)-4-((4-(3- chlorophenyl)-5-(2- hydroxyethylsulfinyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 218

2-(((1s,4s)-4-((4-(2-fluoro- 3-methylphenyl)-5-(2- (methylthio)ethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 219

2-(((1s,4s)-4-((4-(3-chloro- 2-fluorophenyl)-5-(2-(methylsulfinyl)ethyl)-3- phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 220

2-(((1s,4s)-4-((5-(2- (methylsulfinyl)ethyl)-3- phenyl-4-m-tolyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 221

2-(((1s,4s)-4-((4-(3- hydroxyphenyl)-5-(2- (methylthio)ethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 222

2-(((1s,4s)-4-((4-(3- fluorophenyl)-5-(2- (methylthio)ethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 223

2-(((1s,4s)-4-((5-(4- fluorophenyl)-4-phenyl-3- propyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 224

2-(((1s,4s)-4-((3-(4- fluorophenyl)-4-phenyl-5- propyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 225

2-(((1s,4s)-4-((5-(4-chloro- 3-fluorophenyl)-4-phenyl-3-propyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 226

2-(((1s,4s)-4-((3-(4-chloro- 3-fluorophenyl)-4-phenyl-5-propyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 227

2-(((1s,4s)-4-((5-(4- chlorophenyl)-4-phenyl-3- propyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 228

2-(((1s,4s)-4-((3-(4- chlorophenyl)-4-phenyl-5- propyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 229

2-(((1s,4s)-4-((5-(3,4- difluorophenyl)-4-phenyl- 3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 230

2-(((1s,4s)-4-((3-(3,4- difluorophenyl)-4-phenyl- 5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 231

2-(((1s,4s)-4-((5-(2-fluoro- 4-methoxyphenyl)-4- phenyl-3-propyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 232

2-(((1s,4s)-4-((3-(2-fluoro- 4-methoxyphenyl)-4- phenyl-5-propyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 233

2-(((1s,4s)-4-((5-(4- methoxyphenyl)-4-phenyl- 3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 234

2-(((1s,4s)-4-((3-(4- methoxyphenyl)-4-phenyl- 5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 235

2-(((1s,4s)-4-((5-(2-fluoro- 4-methylphenyl)-4-phenyl-3-propyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 236

2-(((1s,4s)-4-((3-(2-fluoro- 4-methylphenyl)-4-phenyl-5-propyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 237

2-(((1s,4s)-4-((4-(3- chlorophenyl)-5-(2- (methylthio)ethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 238

2-(((1s,4s)-4-((5-(2- (methylthio)ethyl)-3,4- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 239

2-(((1s,4s)-4-((5-(2-fluoro- 4-methylphenyl)-3-(2-methoxyethyl)-4-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 240

2-(((1s,4s)-4-((3-(2-fluoro- 4-methylphenyl)-5-(2-methoxyethyl)-4-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 241

2-(((1s,4s)-4-((4-(2-fluoro- 4-methylphenyl)-5-(2-methoxyethyl)-3-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 242

2-(((1s,4s)-4-((4-(2-fluoro- 4-methylphenyl)-5-(2- (methylthio)ethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 243

2-(((1s,4s)-4-((4-(3- methoxyphenyl)-5-(2- (methylthio)ethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 244

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-5-(2- (methylthio)ethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 245

2-(((1r,4r)-4-((3- (cyanomethylthio)-4-(3- methoxyphenyl)-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 246

2-(((1s,4s)-4-((5- (cyanomethylthio)-4-(3- methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 247

2-(((1s,4s)-4-((3-(2- methoxyethyl)-5-(3- methoxyphenyl)-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 248

2-(((1s,4s)-4-((5-(2- methoxyethyl)-3-(3- methoxyphenyl)-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 249

2-(((1s,4s)-4-((4-(3-chloro- 2-fluorophenyl)-5-(2-(methylsulfonyl)ethyl)-3- phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 250

2-(((1s,4s)-4-((5-(2- aminoethylthio)-4-phenyl- 3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 251

2-(((1s,4s)-4-((5-(2- hydroxyethyl)-3,4- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 252

2-(((1s,4s)-4-((5-(2- hydroxyethyl)-4-(3- methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 253

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-5-(2- hydroxyethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 254

2-(((1s,4s)-4-((4-(3- fluorophenyl)-5-(2- hydroxyethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 255

2-(((1s,4s)-4-((3-(4- fluorophenyl)-5-(2- hydroxyethylthio)-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 256

2-(((1s,4s)-4-((5-(4- fluorophenyl)-3-(2- hydroxyethylthio)-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 257

2-(((1s,4s)-4-((5- (cyanomethylthio)-4- phenyl-3-p-tolyl-1H- pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 258

2-(((1s,4s)-4-((5- (cyanomethylthio)-3-(4- fluorophenyl)-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 259

2-(((1s,4s)-4-((3-(2- cyanoethyl)-4,5-diphenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 260

2-(((1s,4s)-4-((5-(2- cyanoethyl)-3,4-diphenyl- 1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 261

2-(((1s,4s)-4-((3-(2- cyanoethyl)-4-(3- methoxyphenyl)-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 262

2-(((1s,4s)-4-((5-(2- cyanoethyl)-4-(3- methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 263

2-(((1s,4s)-4-((5-(2- cyanoethyl)-4-(3- hydroxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 264

2-(((1s,4s)-4-((4-(3- chlorophenyl)-3-(2- cyanoethyl)-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 265

2-(((1s,4s)-4-((4-(3- chlorophenyl)-5-(2- cyanoethyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 266

2-(((1s,4s)-4-((3-(2- cyanoethyl)-4-(3- fluorophenyl)-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 267

2-(((1s,4s)-4-((5-(2- cyanoethyl)-4-(3- fluorophenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 268

2-(((1s,4s)-4-((5-(2- cyanoethyl)-4-(3- hydroxyphenyl)-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 269

2-(((1s,4s)-4-((4-(3-chloro- 2-fluorophenyl)-3-(2-cyanoethyl)-5-phenyl-1H- pyrazol-1- yl)methyl)cyclohexyl) methoxy)aceticacid 270

2-(((1s,4s)-4-((4-(3-chloro- 2-fluorophenyl)-5-(2-cyanoethyl)-3-phenyl-1H- pyrazol-1- yl)methyl)cyclohexyl) methoxy)aceticacid 271

2-(((1s,4s)-4-((5-(3- hydroxypropyl)-3,4- diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 272

2-(((1s,4s)-4-((5-(3- hydroxypropyl)-4-(3- methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 273

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-5-(3- hydroxypropyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 274

2-(((1s,4s)-4-((4-(3- fluorophenyl)-5-(3- hydroxypropyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 275

2-(((1s,4s)-4-((4-(3- chlorophenyl)-5- (cyanomethylthio)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 276

2-(((1s,4s)-4-((4-(3-chloro- 2-fluorophenyl)-5-(2-hydroxyethyl)-3-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 277

2-(((1r,4r)-4-((3-(2-amino- 2-oxoethoxy)-4-(3- methoxyphenyl)-5-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl)) methoxy)acetic acid 278

2-(((1s,4s)-4-((5-(2-amino- 2-oxoethoxy)-4-(3- methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 279

2-(((1r,4r)-4-((3-(2-amino- 2-oxoethoxy)-4-(2-fluoro-3-methoxyphenyl)-5- phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 280

2-(((1s,4s)-4-((5-(2-amino- 2-oxoethoxy)-4-(2-fluoro-3-methoxyphenyl)-3- phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 281

2-(((1s,4s)-4-((4-(3-chloro- 2-fluorophenyl)-5-(3-hydroxypropyl)-3-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 282

2-(((1s,4s)-4-((4-(3- chlorophenyl)-5-(3- hydroxypropyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 283

2-(((1s,4s)-4-((5- (cyanomethoxy)-4-(3- methoxyphenyl)-3-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 284

2-(((1s,4s)-4-((3-(3,4- difluorophenyl)-5-ethyl-4- phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 285

2-(((1s,4s)-4-((5-(2-fluoro- 4-methylphenyl)-3-(2-hydroxyethyl)-4-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 286

2-(((1s,4s)-4-((5-(2-fluoro- 4-methylphenyl)-3-methyl-4-phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 287

2-(((1s,4s)-4-((3-(2-fluoro- 4-methylphenyl)-5-(2-hydroxyethyl)-4-phenyl- 1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 288

2-(((1s,4s)-4-((5-(3- hydroxypropyl)-4-phenyl- 3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 289

2-(((1s,4s)-4-((3-(3- hydroxypropyl)-4-phenyl- 5-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 290

2-(((1s,4s)-4-((5-(2- (methylsulfonyl)ethyl)-4- phenyl-3-p-tolyl-1H-pyrazol-1- yl)methyl)cyclohexyl) methoxy)acetic acid 291

2-(((1s,4s)-4-((3-(2-fluoro- 4-methylphenyl)-5-(2-(methylsulfonyl)ethyl)-4- phenyl-1H-pyrazol-1- yl)methyl)cyclohexyl)methoxy)acetic acid 292

2-(((1s,4s)-4-((5-(2- hydroxyethyl)-4-phenyl-3- p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl) methoxy)acetic acid 293

2-(((1s,4s)-4-((1-p-tolyl- 4,5-dihydro-3H- benzo[e]indazol-3-yl)methyl)cyclohexyl) methoxy)acetic acid

Additionally, individual compounds and chemical genera of the presentinvention, for example those compounds found in TABLE A includingdiastereoisomers and enantiomers thereof, encompass all pharmaceuticallyacceptable salts, solvates and particularly hydrates, thereof.

The compounds of the Formula Ia of the present invention may be preparedaccording to relevant published literature procedures that are used byone skilled in the art. Exemplary reagents and procedures for thesereactions appear hereinafter in the working Examples.

Protection and deprotection may be carried out by procedures generallyknown in the art (see, for example, Greene, T. W. and Wuts, P. G. M.,Protecting Groups in Organic Synthesis, 3^(rd) Edition, 1999 [Wiley];incorporated herein by reference in its entirety).

It is understood that the present invention embraces eachdiastereoisomer, each enantiomer and mixtures thereof of each compoundand generic formulae disclosed herein just as if they were eachindividually disclosed with the specific stereochemical designation foreach chiral carbon. Separation of the individual isomers (such as, bychiral HPLC, recrystallization of diastereoisomeric mixtures and thelike) or selective synthesis (such as, by enantiomeric selectivesyntheses and the like) of the individual isomers is accomplished byapplication of various methods which are well known to practitioners inthe art.

Indications and Methods of Prophylaxis and/or Treatment

In addition to the foregoing beneficial uses for the modulators of PGI2receptor activity disclosed herein, the compounds disclosed herein areuseful in the treatment of several additional diseases and disorders,and in the amelioration of symptoms thereof. Without limitation, theseinclude the following:

1. Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) has a multifactorial pathobiology.Vasoconstriction, remodeling of the pulmonary vessel wall, andthrombosis contribute to increased pulmonary vascular resistance in PAH(Humbert et al., J. Am. Coll, Cardiol., 2004, 43:13S-24S.)

The compounds of the present invention disclosed herein are useful inthe treatment of pulmonary arterial hypertension (PAH) and symptomsthereof. PAH shall be understood to encompass the following forms ofpulmonary arterial hypertension described in the 2003 World HealthOrganization (WHO) clinical classification of pulmonary arterialhypertension: idiopathic PAH (IPAH); familial PAH (FPAH); PAH associatedwith other conditions (APAH), such as PAH associated with collagenvascular disease, PAH associated with congenital systemic-to-pulmonaryshunts, PAH associated with portal hypertension, PAH associated with HIVinfection, PAH associated with drugs or toxins, or PAH associated withOther; and PAH associated with significant venous or capillaryinvolvement.

Idiopathic PAH refers to PAH of undetermined cause.

Familial PAH refers to PAH for which hereditary transmission issuspected or documented.

PAH associated with collagen vascular disease shall be understood toencompass PAH associated with scleroderma, PAH associated with CREST(calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction,sclerodactyly, and telangiectasias) syndrome, PAH associated withsystemic lupus erythematosus (SLE), PAH associated with rheumatoidarthritis, PAH associated with Takayasu's arteritis, PAH associated withpolymyositis, and PAH associated with dermatomyositis.

PAH associated with congenital systemic-to-pulmonary shunts shall beunderstood to encompass PAH associated with atrial septic defect (ASD),PAH associated with ventricular septic defect (VSD) and PAH associatedwith patent ductus arteriosus.

PAH associated with drugs or toxins shall be understood to encompass PAHassociated with ingestion of aminorex, PAH associated with ingestion ofa fenfluramine compound (e.g., PAH associated with ingestion offenfluramine or PAH associated with ingestion of dexfenfluramine), PAHassociated with ingestion of certain toxic oils (e.g., PAH associatedwith ingestion of rapeseed oil), PAH associated with ingestion ofpyrrolizidine alkaloids (e.g., PAH associated with ingestion of bushtea) and PAH associated with ingestion of monocrotaline.

PAH associated with Other shall be understood to encompass PAHassociated with a thyroid disorder, PAH associated with glycogen storagedisease, PAH associated with Gaucher disease, PAH associated withhereditary hemorrhagic telangiectasia, PAH associated with ahemoglobinopathy, PAH associated with a myeloproliferative disorder, andPAH associated with splenectomy.

PAH associated with significant venous or capillary involvement shall beunderstood to encompass PAH associated with pulmonary veno-occlusivedisease (PVOD) and PAH associated with pulmonary capillaryhemangiomatosis (PCH).

(See, e.g., Simonneau et al., J. Am. Coll. Cardiol., 2004, 43:5S-12S;McGoon et al, Chest, 2004, 126:14S-34S; Rabinovitch, Annu. Rev. Pathol.Mech. Dis., 2007, 2:369-399; McLaughlin et al., Circulation, 2006,114:1417-1431; Strauss et al., Clin. Chest. Med., 2007, 28:127-142;Taichman etaL., Clin. Chest. Med., 2007, 28:1-22.)

Evidence for the association of PAH with scleroderma and the beneficialeffect of an agonist of the PGI2 receptor on PAH is given by Badesch etal. (Badesch et al., Ann. Intern. Med., 2000, 132:425-434). Evidence forthe association of PAH with the collagen vascular diseases mixedconnective tissue disease (MCTD), systemic lupus erythematosus (SLE),Sjögren's syndrome and CREST syndrome and the beneficial effect of anagonist of the PGI2 receptor on PAH is given by Humbert et al. (Eur.Respir. J., 1999, 13:1351-1356). Evidence for the association of PAHwith CREST syndrome and the beneficial effect of an agonist of the PGI2receptor on PAH is given by Miwa et al. (Int. Heart J., 2007,48:417-422). Evidence for the association of PAH with SLE and thebeneficial effect of an agonist of the PGI2 receptor on PAH is given byRobbins et al. (Chest, 2000, 117:14-18). Evidence for the association ofPAH with HIV infection and the beneficial of an agonist of the PGI2receptor on PAH is given by Aguilar et al. (Am. J. Respir. Crit. CareMed., 2000, 162:1846-1850). Evidence for the association of PAH withcongenital heart defects (including ASD, VSD and patent ductusarteriosus) and the beneficial effect of an agonist of the PGI2 receptoron PAH is given by Rosenzweig et al. (Circulation, 1999, 99:1858-1865).Evidence for the association of PAH with fenfluramine and withdexfenfluramine, anorexigens, is given by Archer et al. (Am. J. Respir.Crit. Care Med., 1998, 158:1061-1067). Evidence for the association ofPAH with hereditary hemorrhagic telangiectasia is given by McGoon et al.(Chest, 2004, 126:14-34). Evidence for the association of PAH withsplenectomy is given by Hoeper et al. (Ann. Intern. Med., 1999,130:506-509). Evidence for the association of PAH with portalhypertension and the beneficial effect of an agonist of the PGI2receptor on PAH is given by Hoeper et al. (Eur. Respir. J., 2005,25:502-508).

Symptoms of PAH include dyspnea, angina, syncope and edema (McLaughlinet al., Circulation, 2006, 114:1417-1431). The compounds of the presentinvention disclosed herein are useful in the treatment of symptoms ofPAH.

Tawara et al. have demonstrated that long-term inhibition of Rho-kinase,an effector of the small GTPase Rho, ameliorates monocrotaline-inducedPAH in rats and hypoxia-induced PAH in mice. The same group alsoreported that prostacyclin and its oral analog, beraprost sodium (BPS),may lack direct inhibitory effect on Rho-kinase in vitro, suggestingthat combination therapy with a Rho-kinase inhibitor and BPS iseffective for the treatment of PAH. Thus, male Sprague-Dawley rats weregiven a s.c. injection of monocrotaline (60 mg/kg) and maintained withor without the treatment with a Rho-kinase inhibitor, fasudil (30mg/kg/day), BPS (200 μg/kg/day), or a combination of both drugs forthree weeks. The combination therapy, when compared with eachmonotherapy, showed significantly more improvement in PAH, rightventricular hypertrophy, and pulmonary medial thickness without anyadverse effects. (See, Tawara et al, Journal of CardiovascularPharmacology (2007), 50(2), 195-200.)

The PGI2 receptor agonists disclosed herein, alone or in combinationwith a Rho-kinase inhibitor, are useful in the treatment of pulmonaryarterial hypertension (PAH) and symptoms thereof.

The enzyme tryptophan hydroxylase (TPH), has two known isoforms: TPH1,which is expressed in the periphery, and TPH2, which is expressedprimarily in the brain. Mice genetically deficient for the TPH1 gene(“knockout mice”) have been reported. In one case, the mice reportedlyexpressed normal amounts of serotonin in classical serotonergic brainregions, but largely lacked serotonin in the periphery. Walther, D. J.,et al., Science 299:76 (2003). In another, the knockout mice exhibitedabnormal cardiac activity, which was attributed to a lack of peripheralserotonin. Cote, F., et al., PNAS 100(23):13525-13530 (2003).

Recently, TPH knockout mice were studied in a hypoxia-induced pulmonaryarterial hypertension model. Morecroft, I., et al., Hypertension49:232-236 (2007). The results of those studies suggest that TPH1 andperipheral serotonin play an essential role in the development ofhypoxia-induced elevations in pulmonary pressures and hypoxia-inducedpulmonary vascular remodeling.

The PGI2 receptor agonists disclosed herein, alone or in combinationwith a tryptophan hydroxylase inhibitor, are useful in the treatment ofpulmonary arterial hypertension (PAH) and symptoms thereof.

2. Antiplatelet Therapies (Conditions Related to Platelet Aggregation)

Antiplatelet agents (antiplatelets) are prescribed for a variety ofconditions. For example, in coronary artery disease they are used tohelp prevent myocardial infarction or stroke in patients who are at riskof developing obstructive blood clots (e.g., coronary thrombosis).

In a myocardial infarction (“MI” or “heart attack”), the heart muscledoes not receive enough oxygen-rich blood as a result of a blockage inthe coronary blood vessels. If taken while an attack is in progress orimmediately afterward (preferably within 30 min), antiplatelets canreduce the damage to the heart.

A transient ischemic attack (“TIA” or “mini-stroke”) is a briefinterruption of oxygen flow to the brain due to decreased blood flowthrough arteries, usually due to an obstructing blood clot. Antiplateletdrugs have been found to be effective in preventing TIAs.

Angina is a temporary and often recurring chest pain, pressure ordiscomfort caused by inadequate oxygen-rich blood flow (ischemia) tosome parts of the heart. In patients with angina, antiplatelet therapycan reduce the effects of angina and the risk of myocardial infarction.

Stroke is an event in which the brain does not receive enoughoxygen-rich blood, usually due to blockage of a cerebral blood vessel bya blood clot. In high-risk patients, taking antiplatelets regularly hasbeen found to prevent the formation of blood clots that cause first orsecond strokes.

Angioplasty is a catheter based technique used to open arteriesobstructed by a blood clot. Whether or not stenting is performedimmediately after this procedure to keep the artery open, antiplateletscan reduce the risk of forming additional blood clots following theprocedure(s).

Coronary bypass surgery is a surgical procedure in which an artery orvein is taken from elsewhere in the body and grafted to a blockedcoronary artery, rerouting blood around the blockage and through thenewly attached vessel. After the procedure, antiplatelets can reduce therisk of secondary blood clots.

Atrial fibrillation is the most common type of sustained irregular heartrhythm (arrhythmia). Atrial fibrillation affects about two millionAmericans every year. In atrial fibrillation, the atria (the heart'supper chambers) rapidly fire electrical signals that cause them toquiver rather than contract normally. The result is an abnormally fastand highly irregular heartbeat. When given after an episode of atrialfibrillation, antiplatelets can reduce the risk of blood clots formingin the heart and traveling to the brain (embolism).

There is evidence that a PGI2 receptor agonist will inhibit plateletaggregation and thus be a potential treatment as an antiplatelet therapy(see, e.g., Moncada et al., Lancet, 1977, 1:18-20). It has been shownthat genetic deficiency of the PGI2 receptor in mice leads to anincreased propensity towards thrombosis (Murata et al., Nature, 1997,388:678-682).

PGI2 receptor agonists can be used to treat, for example, claudicationor peripheral artery disease as well as cardiovascular complications,arterial thrombosis, atherosclerosis, vasoconstriction caused byserotonin, ischemia-reperfusion injury, and restenosis of arteriesfollowing angioplasty or stent placement. (See, e.g., Fetalvero et al.,Prostaglandins Other Lipid Mediat., 2007, 82:109-118; Arehart et al.,Curr. Med. Chem., 2007, 14:2161-2169; Davi et al., N. Engl. J. Med.,2007, 357:2482-2494; Fetalvero et al., Am. J. Physiol. Heart. Circ.Physiol., 2006, 290:H1337-H1346; Murata et al., Nature, 1997,388:678-682; Wang et al., Proc. Natl. Acad. Sci. USA, 2006,103:14507-14512; Xiao et a., Circulation, 2001, 104:2210-2215; McCormicket al., Biochem. Soc. Trans., 2007, 35:910-911; Arehart et al., Circ.Res., 2008, 102(8), 986-93.)

PGI2 receptor agonists can also be used alone or in combination withthrombolytic therapy, for example, tissue-type plasminogen activator(t-PA), to provide cardioprotection following MI or postischemicmyocardial dysfunction or protection from ischemic injury duringpercutaneous coronary intervention, and the like, includingcomplications resulting therefrom. PG12 receptor agonists can also beused in antiplatelet therapies in combination with, for example,alpha-tocopherol (vitamin E), echistatin (a disintegrin) or, in statesof hypercoagulability, heparin. (See, e.g., Chan., J. Nutr., 1998,128:1593-1596; Mardla et al., Platelets, 2004, 15:319-324; Bernabei etal., Ann. Thorac. Surg., 1995, 59:149-153; Gainza et al., J. Nephrol.,2006, 19:648-655.)

The PGI12 receptor agonists disclosed herein provide beneficialimprovement in microcirculation to patients in need of antiplatelettherapy by antagonizing the vasoconstrictive products of the aggregatingplatelets in, for example and not limited to the indications describedabove. Accordingly, in some embodiments, the present invention providesmethods for reducing platelet aggregation in a patient in need thereof,comprising administering to the patient a composition comprising a PGI2receptor agonist disclosed herein. In further embodiments, the presentinvention provides methods for treating coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke, atrialfibrillation, or a symptom of any of the foregoing in a patient in needof the treatment, comprising administering to the patient a compositioncomprising a PGI2 receptor agonist disclosed herein.

In further embodiments, the present invention provides methods forreducing risk of blood clot formation in an angioplasty or coronarybypass surgery patient, or a patient suffering from atrial fibrillation,comprising administering to the patient a composition comprising a PGI2receptor agonist disclosed herein at a time where such risk exists.

3. Atherosclerosis

Atherosclerosis is a complex disease characterized by inflammation,lipid accumulation, cell death and fibrosis. It is the leading cause ofmortality in many countries, including the United States.Atherosclerosis, as the term is used herein, shall be understood toencompass disorders of large and medium-sized arteries that result inthe progressive accumulation within the intima of smooth muscle cellsand lipids.

It has been shown that an agonist of the PGI2 receptor can conferprotection from atherosclerosis, such as from atherothrombosis (Arehartet al., Curr. Med. Chem., 2007, 14:2161-2169; Stitham et al.,Prostaglandins Other Lipid Mediat., 2007, 82:95-108; Fries et a.,Hematology Am. Soc. Hematol. Educ. Program, 2005, 445-451; Egan et al.,Science, 2004, 306:1954-1957; Kobayashi et al., J. Clin. Invest., 2004,114:784-794; Arehart et al., Circ. Res., 2008, 102(8), 986-93).

It has been shown that defective PGI2 receptor signaling appears toaccelerate atherothrombosis in humans, i.e. that an agonist of the PGI2receptor can confer protection from atherothrombosis in humans (Arehartet al., Circ. Res., 2008, 102(8), 986-93).

The compounds of the present invention disclosed herein are useful inthe treatment of atherosclerosis, and the treatment of the symptomsthereof. Accordingly, in some embodiments, the present inventionprovides methods for treating atherosclerosis in a patient in need ofthe treatment, comprising administering to the patient a compositioncomprising a PGI2 receptor agonist disclosed herein. In furtherembodiments, methods are provided for treating a symptom ofatherosclerosis in a patient in need of the treatment, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein.

4. Asthma

Asthma is a lymphocyte-mediated inflammatory airway disordercharacterized by airway eosinophilia, increased mucus production bygoblet cells, and structural remodeling of the airway wall. Theprevalence of asthma has dramatically increased worldwide in recentdecades. It has been shown that genetic deficiency of the PGI2 receptorin mice augments allergic airway inflammation (Takahashi et al., Br JPharmacol, 2002, 137:315-322). It has been shown that an agonist of thePGI2 receptor can suppress not only the development of asthma when givenduring the sensitization phase, but also the cardinal features ofexperimental asthma when given during the challenge phase (Idzko et a.,J. Clin. Invest., 2007, 117:464-472; Nagao et al., Am. J. Respir. CellMol. Biol., 2003, 29:314-320), at least in part through markedlyinterfering with the function of antigen-presenting dendritic cellswithin the airways (Idzko et al., J. Clin. Invest., 2007, 117:464-472;Zhou et al., J. Immunol., 2007, 178:702-710; Jaffar et al., J. Immunol.,2007, 179:6193-6203; Jozefowski et al., Int. Immunopharmacol., 2003,3:865-878). These cells are crucial for both the initiation and themaintenance phases of allergic asthma, as depletion of airway dendriticcells during secondary challenge in sensitized mice abolished allcharacteristic features of asthma, an effect that could be completelyrestored by adoptive transfer of wild-type dendritic cells (van Rijt etal., J. Exp. Med., 2005, 201:981-991). It has also been shown that anagonist of the PGI2 receptor can inhibit proinflammatory cytokinesecretion by human alveolar macrophages (Raychaudhuri et al., J. Biol.Chem., 2002, 277:33344-33348). The compounds of the present inventiondisclosed herein are useful in the treatment of asthma, and thetreatment of the symptoms thereof. Accordingly, in some embodiments, thepresent invention provides methods for treating asthma in a patient inneed of the treatment, comprising administering to the patient acomposition comprising a PGI2 receptor agonist disclosed herein. Infurther embodiments, methods are provided for treating a symptom ofasthma in a patient in need of the treatment, comprising administeringto the patient a composition comprising a PGI2 receptor agonistdisclosed herein.

5. Diabetic-Related Pathologies

Although hyperglycemia is the major cause for the pathogenesis ofdiabetic complications such as diabetic peripheral neuropathy (DPN),diabetic nephropathy (DN) and diabetic retinopathy (DR), enhancedvasoconstriction and platelet aggregation in diabetic patients has alsobeen implicated to play a role in disease progression (Cameron et al,Naunyn Schmiedebergs Arch. Pharmacol., 2003, 367:607-614). Agonists ofthe PGI2 receptor promote vasodilation and inhibit platelet aggregation.Improving microvascular blood flow is able to benefit diabeticcomplications (Cameron, Diabetologia, 2001, 44:1973-1988).

It has been shown that an agonist of the PGI2 receptor can prevent andreverse motor and sensory peripheral nerve conduction abnormalities instreptozotocin-diabetic rats (Cotter et al., Naunyn Schmiedebergs Arch.Pharmacol., 1993, 347:534-540). Further evidence for the beneficialeffect of an agonist of the PGI2 receptor in the treatment of diabeticperipheral neuropathy is given by Hotta et al. (Diabetes, 1996,45:361-366), Ueno et al. (Jpn. J. Pharmacol., 1996, 70:177-182), Ueno etal. (Life Sci., 1996, 59:PL105-PL110), Hotta et al. (Prostaglandins,1995, 49:339-349), Shindo et al. (Prostaglandins, 1991, 41:85-96), Okudaet al. (Prostaglandins, 1996, 52:375-384), and Koike et al. (FASEB J.,2003, 17:779-781). Evidence for the beneficial effect of an agonist ofthe PGI2 receptor in the treatment of diabetic nephropathy is given byOwada et al. (Nephron, 2002, 92:788-796) and Yamashita et al. (DiabetesRes. Clin. Pract., 2002, 57:149-161). Evidence for the beneficial effectof an agonist of the PGI2 receptor in the treatment of diabeticretinopathy is given by Yamagishi et al. (Mol. Med., 2002, 8:546-550),Burnette et al. (Exp. Eye Res., 2006, 83:1359-1365), and Hotta et al.(Diabetes, 1996, 45:361-366). It has been shown that an agonist of thePGI2 receptor can reduce increased tumor necrosis factor-α (TNF-α)levels in diabetic patients, implying that an agonist of the PGI2receptor may contribute to the prevention of progression in diabeticcomplications (Fujiwara et a., Exp. Clin. Endocrinol. Diabetes, 2004,112:390-394).

6. Glaucoma

Evidence that topical administration of an agonist of the PGI2 receptorcan result in a decrease in intraocular pressure (IOP) in rabbits anddogs and thereby have beneficial effect in the treatment of glaucoma isgiven by Hoyng et at (Hoyng et at, Invest. Ophthalmol. Vis. Sci., 1987,28:470-476).

7. Hypertension

Agonists of the PGI2 receptor have been shown to have activity forregulation of vascular tone, for vasodilation, and for amelioration ofpulmonary hypertension (see, e.g., Strauss et at, Clin Chest Med, 2007,28:127-142; Driscoll et al., Expert Opin. Pharmacother., 2008, 9:65-81).Evidence for a beneficial effect of an agonist of the PGI2 receptor inthe treatment of hypertension is given by Yamada et al. (Peptides, 2008,29:412-418). Evidence that an agonist of the PGI2 receptor can protectagainst cerebral ischemia is given by Dogan et al. (Gen. Pharmacol.,1996, 27:1163-1166) and Fang et a. (J. Cereb. Blood Flow Metab., 2006,26:491-501).

8. Anti-Inflammation Therapies

Anti-inflammation agents are prescribed for a variety of conditions. Forexample, in an inflammatory disease they are used to interfere with andthereby reduce an underlying deleterious There is evidence that a PGI2receptor agonist can inhibit inflammation and thus be a potentialtreatment as an anti-inflammation therapy. It has been shown that anagonist of the PGI2 receptor can inhibit pro-inflammatory cytokine andchemokine (interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α),IL-la, IL-6, macrophage inflammatory protein-1alpha (MIP-1α), monocytechemoattractant protein-1 (MCP-1)) production and T cell stimulatoryfunction of dendritic cells (Jozefowski et al., Int. Immunopharmacol.,2003, 865-878; Zhou et al., J. Immunol., 2007, 178:702-710; Nagao etal., Am. J. Respir. Cell Mol. Biol., 2003, 29:314-320; Idzko et al., J.Clin. Invest., 2007, 117:464-472). It has been shown that an agonist ofthe PGI2 receptor can inhibit pro-inflammatory cytokine (TNF-α, IL-β,IL-6, granulocyte macrophage stimulating factor (GM-CSF)) production bymacrophages (Raychaudhuri et al, J. Biol. Chem., 2002, 277:33344-33348;Czeslick et al., Eur. J. Clin. Invest., 2003, 33:1013-1017; Di Renzo etal., Prostaglandin Leukot. Essent. Fatty Acids, 2005, 73:405-410;Shinomiya et a., Biochem. Pharmacol., 2001, 61:1153-1160). It has beenshown that an agonist of the PGI2 receptor can stimulateanti-inflammatory cytokine (IL-10) production by dendritic cells(Jozefowski et at, Int. Immunopharmacol., 2003, 865-878; Zhou et al., J.Immunol., 2007, 178:702-710). It has been shown that an agonist of thePGI2 receptor can stimulate anti-inflammatory cytokine (IL-10)production by macrophages (Shinomiya et al., Biochem. Pharmacol., 2001,61:1153-1160). It has been shown that an agonist of the PGI2 receptorcan inhibit a chemokine (CCL17)-induced chemotaxis of leukocytes (CD4⁺Th2 T cells) (Jaffar et al., J. Immunol., 2007, 179:6193-6203). It hasbeen shown that an agonist of the PGI2 receptor can confer protectionfrom atherosclerosis, such as from atherothrombosis (Arehart et al.,Curr. Med. Chem., 2007, 14:2161-2169; Stitham et al., ProstaglandinsOther Lipid Mediat., 2007, 82:95-108; Fries et al., Hematology Am. Soc.Hematol. Educ. Program, 2005, 445-451; Egan et al., Science, 2004,306:1954-1957; Kobayashi et al., J. Clin. Invest., 2004, 114:784-794;Arehart et al., Circ. Res., 2008, 102(8), 986-93). It has been shownthat an agonist of the PGI2 receptor can attenuate asthma (Idzko et al.,J. Clin. Invest., 2007, 117:464-472; Jaffar et al., J. Immunol., 2007,179:6193-6203; Nagao et alt, Am. J. Respir. Cell. Mol. Biol., 2003,29:314-320). It has been shown that an agonist of the PGI2 receptor candecrease TNF-α production in type 2 diabetes patients (Fujiwara et al.,Exp. Clin. Endocrinol. Diabetes, 2004, 112:390-394; Goya et al.,Metabolism, 2003, 52:192-198). It has been shown that an agonist of thePGI2 receptor can inhibit ischemia-reperfusion injury (Xiao et al.,Circulation, 2001, 104:2210-2215). It has been shown that an agonist ofthe PGI2 receptor can inhibit restenosis (Cheng et al, Science, 2002,296:539-541). It has been shown that an agonist of the PGI2 receptor canattenuate pulmonary vascular injury and shock in a rat model of septicshock (Harada et al., Shock, 2008, Feb. 21 Epub ahead of print). It hasbeen shown that an agonist of the PGI2 receptor can reduce the serumlevels of TNF-α in vivo in patients with rheumatoid arthritis, and thisis associated with improvement in the clinical course of the disease(Gao et al., Rheumatol. Int., 2002, 22:45-51; Boehme et al., Rheumatol.Int., 2006, 26:340-347).

The compounds of the present invention disclosed herein providebeneficial reduction of inflammation. The compounds of the presentinvention disclosed herein provide beneficial reduction of a deleteriousinflammatory response associated with an inflammatory disease.Accordingly, in some embodiments, the present invention provides methodsfor reducing inflammation in a patient in need thereof, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein. In some embodiments, the present inventionprovides methods for decreasing IL-12, TNF-α, IL-1α, IL-1β, IL-6, MIP-1αor MCP-1 production in a patient in need thereof, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein. In some embodiments, the present inventionprovides methods for decreasing TNF-α production in a patient in needthereof, comprising administering to the patient a compositioncomprising a PGI2 receptor agonist disclosed herein. In someembodiments, the present invention provides methods for increasing IL-10production in a patient in need thereof, comprising administering to thepatient a composition comprising a PGI2 receptor agonist disclosedherein. In some embodiments, the present invention provides methods forreducing a deleterious inflammatory response associated with aninflammatory disease in a patient in need thereof, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein. In some embodiments, the present inventionprovides methods for treating an inflammatory disease or a symptomthereof in a patient in need of the treatment comprising administeringto the patient a composition comprising a PGI2 receptor agonistdisclosed herein. In some embodiments, the present invention providesmethods for treating an inflammatory disease or a symptom thereof in apatient in need of the treatment comprising administering to the patienta composition comprising a PGI2 receptor agonist disclosed herein. Insome embodiments, the present invention provides methods for treating aninflammatory disease or a symptom thereof in a patient in need of thetreatment comprising administering to the patient a compositioncomprising a PGI2 receptor agonist disclosed herein, wherein theinflammatory disease is selected from the group consisting of psoriasis,psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplantrejection, multiple sclerosis, systemic lupus erythematosus (SLE),ulcerative colitis, ischemia-reperfusion injury, restenosis,atherosclerosis, acne, diabetes (including type 1 diabetes and type 2diabetes), sepsis, chronic obstructive pulmonary disease (COPD), andasthma.

9. Traumatic Brain Injury

Prostacyclin production is known to increase after brain trauma, and ina recent study, the importance of prostacyclin for posttraumatichemodynamic alterations and neuron survival was investigated.Prostacyclin receptor-deficient (IP^(−/−)) mice were compared to micewith functional prostacyclin receptors (IP^(+/+)) after a controlledcortical injury. Contusion volume was increased in IP^(−/−) micecompared with IP^(+/+) mice. Three hours after trauma, cortical bloodflow was decreased in the injured cortex of both groups and thereduction in blood flow in the cortex of the IP^(−/−) mice persistedfrom 3 to 24 h, whereas blood flow approached normal values in theIP^(+/+) mice after 24 h. (See, e.g., Lundblad et al. Journal ofCerebral Blood Flow & Metabolism (2008) 28, 367-376).

The PGI2 receptor agonists disclosed herein provide beneficialimprovement in neuron survival after brain trauma. Accordingly, in someembodiments, the present invention provides methods for treating atraumatic brain injury in a patient in need thereof, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein.

Pharmaceutical Compositions

A further aspect of the present invention pertains to pharmaceuticalcompositions comprising one or more compounds as described herein andone or more pharmaceutically acceptable carriers. Some embodimentspertain to pharmaceutical compositions comprising a compound of thepresent invention and a pharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing at least one compoundaccording to any of the compound embodiments disclosed herein and apharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically byuniformly mixing the active compound(s) with liquids or finely dividedsolid carriers, or both, in the required proportions and then, ifnecessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions and syrups. Alternatively, the oral preparations maybe in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20^(th) Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro et al.)

While it is possible that, for use in the prophylaxis or treatment, acompound of the invention may, in an alternative use, be administered asa raw or pure chemical, it is preferable however to present the compoundor active ingredient as a pharmaceutical formulation or compositionfurther comprising a pharmaceutically acceptable carrier.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, subcutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with minimal degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention or a solvate, hydrate orphysiologically functional derivative thereof can be used as activeingredients in pharmaceutical compositions, specifically as PGI2receptor modulators. By the term “active ingredient” is defined in thecontext of a “pharmaceutical composition” and is intended to mean acomponent of a pharmaceutical composition that provides the primarypharmacological effect, as opposed to an “inactive ingredient” whichwould generally be recognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can varywithin wide limits and as is customary and is known to the physician, itis to be tailored to the individual conditions in each individual case.It depends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the compound employed or onwhether an acute or chronic disease state is treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention. Representative dosesof the present invention include, but not limited to, about 0.001 mg toabout 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about25 mg. Multiple doses may be administered during the day, especiallywhen relatively large amounts are deemed to be needed, for example 2, 3or 4 doses. Depending on the individual and as deemed appropriate fromthe patient's physician or caregiver it may be necessary to deviateupward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, on whether anacute or chronic disease state is being treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention and as part of a drugcombination. The dosage regimen for treating a disease condition withthe compounds and/or compositions of this invention is selected inaccordance with a variety factors as cited above. Thus, the actualdosage regimen employed may vary widely and therefore may deviate from apreferred dosage regimen and one skilled in the art will recognize thatdosage and dosage regimen outside these typical ranges can be testedand, where appropriate, may be used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4 part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt, solvate or hydrate of a compound ofthe invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size. The powders and tablets may contain varyingpercentage amounts of the active compound. A representative amount in apowder or tablet may contain from 0.5 to about 90 percent of the activecompound; however, an artisan would know when amounts outside of thisrange are necessary. Suitable carriers for powders and tablets aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavors, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents and thelike.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of thepresent invention or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thecompounds of the present invention as an aerosol can be prepared byprocesses well known to the person skilled in the art. For theirpreparation, for example, solutions or dispersions of the compounds ofthe present invention in water, water/alcohol mixtures or suitablesaline solutions can be employed using customary additives, for examplebenzyl alcohol or other suitable preservatives, absorption enhancers forincreasing the bioavailability, solubilizers, dispersants and othersand, if appropriate, customary propellants, for example include carbondioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane,or dichlorotetrafluoroethane; and the like. The aerosol may convenientlyalso contain a surfactant such as lecithin. The dose of drug may becontrolled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

The compounds according to the invention may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric,tartaric, oxalic, p-toluenesulfonic and the like. Certain compounds ofthe present invention which contain a carboxylic acid functional groupmay optionally exist as pharmaceutically acceptable salts containingnon-toxic, pharmaceutically acceptable metal cations and cations derivedfrom organic bases. Representative metals include, but are not limitedto, aluminium, calcium, lithium, magnesium, potassium, sodium, zinc andthe like. In some embodiments the pharmaceutically acceptable metal issodium. Representative organic bases include, but are not limited to,benzathine (N¹,N²-dibenzylethane-1,2-diamine), chloroprocaine(2-(diethylamino)ethyl 4-(chloroamino)benzoate), choline,diethanolamine, ethylenediamine, meglumine((2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol), procaine(2-(diethylamino)ethyl 4-aminobenzoate), and the like. Certainpharmaceutically acceptable salts are listed in Berge, et al., Journalof Pharmaceutical Sciences, 66:1-19 (1977), incorporated herein byreference in its entirety.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Compounds of the present invention can be converted to “pro-drugs.” Theterm “pro-drugs” refers to compounds that have been modified withspecific chemical groups known in the art and when administered into anindividual these groups undergo biotransformation to give the parentcompound. Pro-drugs can thus be viewed as compounds of the inventioncontaining one or more specialized non-toxic protective groups used in atransient manner to alter or to eliminate a property of the compound. Inone general aspect, the “pro-drug” approach is utilized to facilitateoral absorption. A thorough discussion is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S.Symposium Series; and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference in theirentirety.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one compound according to any of the compoundembodiments disclosed herein, together with at least one knownpharmaceutical agent as described herein and a pharmaceuticallyacceptable carrier.

It is noted that when the PGI2 receptor modulators are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as PGI2receptor modulators, for the treatment of an PGI2-associated disease ordisorder in companionship animals (e.g., cats, dogs, etc.) and inlivestock animals (e.g., cows, chickens, fish, etc.) Those of ordinaryskill in the art are readily credited with understanding the utility ofsuch compounds in such settings.

Hydrates and Solvates

It is understood that when the phrase pharmaceutically acceptable salts,solvates and hydrates is used in referring to a particular formulaherein, it is intended to embrace solvates and/or hydrates of compoundsof the particular formula, pharmaceutically acceptable salts ofcompounds of the particular formula as well as solvates and/or hydratesof pharmaceutically acceptable salts of compounds of the particularformula.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be apparent tothose skilled in the art that the following dosage forms may comprise,as the active component, either a compound of the invention or apharmaceutically acceptable salt or as a solvate or hydrate thereof.Moreover, various hydrates and solvates of the compounds of theinvention and their salts will find use as intermediates in themanufacture of pharmaceutical compositions. Typical procedures formaking and identifying suitable hydrates and solvates, outside thosementioned herein, are well known to those in the art; see for example,pages 202-209 of K. J. Guillory, “Generation of Polymorphs, Hydrates,Solvates, and Amorphous Solids,” in: Polymorphism in PharmaceuticalSolids, ed. Harry G. Brittan, Vol. 95, Marcel Dekker, Inc., New York,1999, incorporated herein by reference in its entirety. Accordingly, oneaspect of the present invention pertains to hydrates and solvates ofcompounds of Formula Ia and/or their pharmaceutical acceptable salts, asdescribed herein, that can be isolated and characterized by methodsknown in the art, such as, thermogravimetric analysis (TGA), TGA-massspectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction(XRPD), Karl Fisher titration, high resolution X-ray diffraction, andthe like. There are several commercial entities that provide quick andefficient services for identifying solvates and hydrates on a routinebasis. Example companies offering these services include WilmingtonPharmaTech (Wilmington, Del.), Avantium Technologies (Amsterdam) andAptuit (Greenwich, Conn.).

Other Utilities

Another object of the present invention relates to radio-labeledcompounds of the present invention that would be useful not only inradio-imaging but also in assays, both in vitro and in vivo, forlocalizing and quantitating the PGI2 receptor in tissue samples,including human and for identifying PGI2 receptor ligands by inhibitionbinding of a radio-labeled compound. It is a further object of thisinvention to develop novel PGI2 receptor assays of which comprise suchradio-labeled compounds.

The present invention embraces isotopically-labeled compounds of thepresent invention. Isotopically or radio-labeled compounds are thosewhich are identical to compounds disclosed herein, but for the fact thatone or more atoms are replaced or substituted by an atom having anatomic mass or mass number different from the atomic mass or mass numbermost commonly found in nature. Suitable radionuclides that may beincorporated in compounds of the present invention include but are notlimited to ²H (also written as D for deuterium), ³H (also written as Tfor tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl,⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I The radionuclide thatis incorporated in the instant radio-labeled compounds will depend onthe specific application of that radio-labeled compound. For example,for in vitro PGI2 receptor labeling and competition assays, compoundsthat incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵ I, ¹³¹I or ³⁵S will generally bemost useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I,¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound of Formula Ia, Ic, Ie, Ig, or Ii that has incorporated at leastone radionuclide; in some embodiments the radionuclide is selected fromthe group consisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Certain isotopically-labeled compounds of the present invention areuseful in compound and/or substrate tissue distribution assays. In someembodiments the radionuclide ³H and/or ¹⁴C isotopes are useful in thesestudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in the Drawings and Examples infra, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.Other synthetic methods that are useful are discussed infra. Moreover,it should be understood that all of the atoms represented in thecompounds of the invention can be either the most commonly occurringisotope of such atoms or the scarcer radio-isotope or nonradioactiveisotope.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. These synthetic methods, for example, incorporatingactivity levels of tritium into target molecules, are as follows:

A. Catalytic Reduction with Tritium Gas: This procedure normally yieldshigh specific activity products and requires halogenated or unsaturatedprecursors.

B. Reduction with Sodium Borohydride [³H]: This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters and the like.

C. Reduction with Lithium Aluminum Hydride [³H]: This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters and the like.

D. Tritium Gas Exposure Labeling: This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H]: This procedure is usuallyemployed to prepare O-methyl or N-methyl (³H) products by treatingappropriate precursors with high specific activity methyl iodide (³H).This method in general allows for higher specific activity, such as forexample, about 70-90 Ci/mmol.

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include:

A. Sandmeyer and like reactions: This procedure transforms an aryl amineor a heteroaryl amine into a diazonium salt, such as a diazoniumtetrafluoroborate salt and subsequently to ¹²⁵I labeled compound usingNa¹²⁵I. A represented procedure was reported by Zhu, G-D. and co-workersin J. Org. Chem., 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols: This procedure allows for theincorporation of ¹²⁵I at the ortho position of a phenol as reported byCollier, T. L. and co-workers in J. Labelled Compd. Radiopharm., 1999,42, S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I: This method isgenerally a two step process. The first step is the conversion of thearyl or heteroaryl bromide to the corresponding tri-alkyltinintermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph₃P)₄]or through an aryl or heteroaryl lithium, in the presence of atri-alkyltinhalide or hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)₃]. Arepresentative procedure was reported by Le Bas, M.-D. and co-workers inJ. Labelled Compd. Radiopharm. 2001, 44, S280-S282.

A radiolabeled PGI2 receptor compound of Formula Ia can be used in ascreening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radio-labeledcompound of Formula Ia” to the PGI2 receptor. Accordingly, the abilityof a test compound to compete with the “radio-labeled compound ofFormula Ia” for the binding to the PGI2 receptor directly correlates toits binding affinity.

The labeled compounds of the present invention bind to the PGI2receptor. In one embodiment the labeled compound has an IC₅₀ less thanabout 500 μM, in another embodiment the labeled compound has an IC₅₀less than about 100 μM, in yet another embodiment the labeled compoundhas an IC₅₀ less than about 10 μM, in yet another embodiment the labeledcompound has an IC₅₀ less than about 1 μM and in still yet anotherembodiment the labeled inhibitor has an IC₅₀ less than about 0.1 μM.

Other uses of the disclosed receptors and methods will become apparentto those skilled in the art based upon, inter alia, a review of thisdisclosure.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES Example 1: Syntheses of Compounds of the Present Invention

Illustrated syntheses for compounds of the present invention are shownin FIGS. 3 through 9 where the symbols have the same definitions as usedthroughout this disclosure.

The compounds of the invention and their syntheses are furtherillustrated by the following examples. The following examples areprovided to further define the invention without, however, limiting theinvention to the particulars of these examples. The compounds describedherein, supra and infra, are named according to the CS ChemDraw UltraVersion 7.0.1, AutoNom version 2.2, or CS ChemDraw Ultra Version 9.0.7.In certain instances common names are used and it is understood thatthese common names would be recognized by those skilled in the art.

Chemistry: Proton nuclear magnetic resonance (¹H NMR) spectra wererecorded on a Bruker Avance-400 equipped with a QNP (Quad Nucleus Probe)or a BBI (Broad Band Inverse) and z-gradient. Chemical shifts are givenin parts per million (ppm) with the residual solvent signal used asreference. NMR abbreviations are used as follows: s=singlet, d=doublet,dd=doublet of doublets, ddd=doublet of doublet of doublets, dt=doubletof triplets, t=triplet, td=triplet of doublets, tt=triplet of triplets,q=quartet, m=multiplet, bs=broad singlet, bt=broad triplet. Microwaveirradiations were carried out using a Smith Synthesizer™ or an EmrysOptimizer™ (Biotage). Thin-layer chromatography (TLC) was performed onsilica gel 60 F₂₅₄ (Merck), preparatory thin-layer chromatography (prepTLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman) andcolumn chromatography was carried out on a silica gel column usingKieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done under reducedpressure on a Büchi rotary evaporator.

LCMS spec: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC systemcontroller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, ShimadzuInc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.

Example 1.1: Preparation of t-Butyl2-(((1s,4s)-4-(Tosyloxymethyl)cyclohexyl)methoxy)acetate Step A:Preparation of (1s,4s)-Diethyl Cyclohexane-1,4-dicarboxylate

To a solution of (1s,4s)-cyclohexane-1,4-dicarboxylic acid (25 g, 145mmol) in ethanol (150 mL) was added concentrated H₂SO₄ (1 mL). Thereaction was refluxed for 16 h, cooled to room temperature andconcentrated. The residue was extracted with EtOAc and saturated NaHCO₃,washed with brine, dried over MgSO₄, and filtered. The filtrate wasconcentrated to provide the title compound as a colorless oil (30.5 g).¹H NMR (400 MHz, CDCl₃) δ ppm 1.25 (t, J=7.14 Hz, 6H), 1.64-1.70 (m,4H), 1.87-1.92 (m, 4H), 2.44-2.46 (m, 2H), 4.11-1.46 (quartet, J=7.12Hz, 4H).

Step B: Preparation of (1s,4s)-Cyclohexane-1,4-diyldimethanol

To a solution of (1s,4s)-diethyl cyclohexane-1,4-dicarboxylate (13.0 g,56.9 mmol) in THF (500 mL) was added lithium aluminum hydride (4.54 g,120 mmol) in portions at 0° C. The mixture was stirred at thattemperature for 2 h and quenched with cold water, filtered andconcentrated to give the title compound as a colorless oil (8.2 g). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.27-1.42 (m, 8H), 1.46-1.54 (m, 2H),3.26-3.31 (m, 4H), 4.27-4.30 (t, J=5.31 Hz, 2H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-(Hydroxymethyl)cyclohexyl)methoxy)acetate

To a solution of (1s,4s)-cyclohexane-1,4-diyldimethanol (18.2 g, 126mmol) in toluene (200 mL) was added NaOH (50% aqueous, 60 mL) andtetrabutylammonium iodide (2.331 g, 6.31 mmol), followed bytert-butyl-2-bromoacetate (20.50 mL, 139 mmol) at room temperature. Thereaction mixture was stirred vigorously at room temperature for 2 h anddiluted with ethyl acetate and water. After separation, the aqueouslayer was extracted with EtOAc (3×30 mL). The combined organic layerswere dried over MgSO₄, concentrated, and purified by silica gel columnchromatography to give the title compound as a colorless oil (13.5 g).¹H NMR (400 MHz, CDCl₃) δ ppm 1.35-1.47 (m, 4H), 1.48 (s, 9H), 1.50-1.60(m, 4H), 1.63-1.74 (m, 1H), 1.79-1.92 (m, 1H), 3.42 (d, J=6.95 Hz, 2H),3.55 (d, J=6.82 Hz, 2H), 3.93 (s, 1H), 3.94 (s, 2H).

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-(Tosyloxymethyl)cyclohexyl)methoxy)acetate

To a solution of tert-butyl2-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methoxy)acetate (12.0 g, 46.4mmol) in dichloromethane (150 mL) were added triethylamine (4.70 g, 46.4mmol) and 4-(dimethylamino)pyridine (0.567 g, 4.64 mmol), followed by4-methylbenzene-1-sulfonyl chloride (8.86 g, 46.4 mmol). The reactionwas stirred at room temperature for 16 h. The solvent was removed andthe residue was extracted with EtOAc/H₂O. The organic extracts weredried over MgSO₄, and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale liquid(9.5 g). LCMS m/z=413.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.28-1.43(m, 4H), 1.46-1.48 (m, 9H), 1.49-1.56 (m, 4H), 1.76-1.91 (m, 2H), 2.45(s, 3H), 3.36 (d, J=6.95 Hz, 2H), 3.92 (d, J=7.05 Hz, 2H), 3.92 (s, 2H),7.35 (d, J=8.46 Hz, 2H), 7.78 (d, J=8.34 Hz, 2H).

Example 1.2: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 95) Step A: Preparation of4-(3-Chlorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazole

To a solution of 2-(3-chlorophenyl)-1-phenylethanone (5 g, 21.67 mmol)in anhydrous THF (10 mL) was added a solution of 1.0 M KO-t-Bu in THF.The reaction was stirred for 15 min at room temperature, then CS₂ (1.782g, 23.41 mmol) was added. After 10 min, iodomethane (6.77 g, 47.7 mmol)was added and the reaction was stirred for 4 h. The reaction was washedwith saturated NaHCO₃ solution and dried over MgSO₄. The filtrate wasconcentrated under reduced pressure and the residue was triturated with10% ethyl acetate. The solid was suspended in ethanol and hydrazinehydrate (5.43 g, 108 mmol) was added at room temperature. The reactionwas refluxed for 4 h. The reaction mixture was concentrated underreduced pressure and the residue was triturated with ethylacetate/hexane to give the title compound as a white solid (4.9 g). LCMSm/z=301.1 [M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of 4-(3-chlorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazole(4.98 g, 16.62 mmol) in DMF (2 mL) was added sodium hydride (0.399 g,16.62 mmol) at 0° C. After stirring for 10 min, tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (6.86 g, 16.62mmol) was added and warmed to 40° C. After stirring for 12 h, themixture was extracted with ethyl acetate. The organic extract wasconcentrated under reduced pressure and the residue was treated with 4.0M HCl for 8 h. The mixture was concentrated under reduced pressure andpurified by HPLC to give the title compound (3.89 g). LCMS m/z=486.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.50 (m, 8H), 1.74 (m, 1H),2.14 (m, 1H), 2.31 (s, 3H), 3.52 (d, J=7.0 Hz, 2H), 3.58 (s, 2H), 4.25(d, J=7.5 Hz, 2H), 7.25-7.51 (m, 9H).

Example 1.3: Preparation of2-(((1s,4s)-4-((4-(3,4-Difluorophenyl)-5-ethoxy-3-phenyl-1-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 80) Step A: Preparation of 3-Phenyl-1H-pyrazol-5(4H)-one

To a solution of propyl 3-oxo-3-phenylpropanoate (10 g, 48.5 mmol) inethanol (100 mL) was added hydrazine hydrate (9.71 g, 194 mmol) at roomtemperature. The reaction was heated to 80° C. for 2 h, cooled to roomtemperature and concentrated. The residue was crystallized from 20%ethyl acetate/hexane to give the title compound (6.58 g). LCMSm/z=161.08 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm, 2.32 (br, 2H),7.32-7.78 (m, 5H), 12.1 (s, 1H).

Step B: Preparation of 5-Ethoxy-3-phenyl-1H-pyrazole

To a solution of 3-phenyl-1H-pyrazol-5(4H)-one (1.0 g, 6.24 mmol),ethanol (0.288 g, 6.24 mmol) and triphenylphosphine (1.638 g, 6.24 mmol)in N-methylmorpholine (7 mL) was added diethylazo dicarboxylate (0.988mL, 6.24 mmol) dropwise at 0° C. The reaction was warmed to roomtemperature and stirred for 2 h. The reaction was poured into H₂O andextracted with ethyl acetate. The extract was dried over MgSO₄ andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give the title compound (0.89 g). LCMSm/z=189.19 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J=4.2 Hz,3H), 4.32 (q, J=4.2 Hz, 2H), 6.45 (s, 1H), 7.41-7.94 (m, 5H), 11.3 (s,1H).

Step C: Preparation of 4-Bromo-5-ethoxy-3-phenyl-1H-pyrazole

To a solution of 5-ethoxy-3-phenyl-1H-pyrazole (1.0 g, 5.31 mmol) indichloromethane (20 mL), was added bromine (0.849 g, 5.31 mmol) dropwiseat room temperature. The reaction was stirred for 2 h, washed withsaturated NaHCO₃ solution and concentrated under reduced pressure. Theresidue was triturated with 10% ethyl acetate/hexane to give the titlecompound as a yellowish solid (1.20 g). LCMS m/z=268.07 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.38 (t, J=4.2 Hz, 3H), 4.39 (q, J=4.2 Hz, 2H),7.45-7.85 (m, 5H), 12.4 (s, 1H).

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-ethoxy-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 4-bromo-5-ethoxy-3-phenyl-1H-pyrazole (1.5 g, 5.62mmol) in DMF (5 mL) was added sodium hydride (0.135 g, 5.62 mmol) atroom temperature. After stirring for 10 min, a solution of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (2.317 g, 5.62mmol) in DMF (1 mL) was added at room temperature. The reaction wasstirred at 45° C. for 8 h. The mixture was poured into H₂O and extractedwith ethyl acetate. The organic extract was dried over MgSO₄ andconcentrated under reduced pressure. The residue was purified by silicagel to give the title compound (1.45 g). LCMS m/z=508.35 [M+H]⁺.

Step E: Preparation of2-(((1s,4s)-4-((4-(3,4-Difluorophenyl)-5-ethoxy-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethoxy-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(110 mg, 0.217 mmol) in dioxane (2 mL) were added3,4-difluorophenylboronic acid (34.2 mg, 0.217 mmol), Pd(PPh₃)₄(12.52mg, 10.84 μmol), and K₂CO₃ (59.9 mg, 0.434 mmol) at room temperature.The reaction was irradiated under microwave for 1.5 h at 150° C. Themixture was filtered and the filtrate was concentrated under reducedpressure. The residue was treated with 4.0 M HCl (5 mL). After stirringfor 10 h, the reaction was concentrated under reduced pressure andpurified by HPLC to give the title compound (85 mg). LCMS m/z=485.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (t, J=4.1 Hz, 3H),1.30-1.41 (m, 8H), 1.63-1.74 (m, 1H), 2.18-2.23 (m, 1H), 3.49 (d, J=7.1Hz, 2H), 3.71 (s, 2H), 3.85 (q, J=4.1 Hz, 2H), 4.12 (d, J=7.4 Hz, 2H),7.76-7.32 (m, 8H).

Example 1.4: Preparation of2-(((1s,4s)-4-((4-(5-Cyano-2-fluorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 79) Step A: Preparation of5-(Methylthio)-3-phenyl-1H-pyrazole

To a solution of acetophenone (5.0 g, 41.6 mmol) and CS₂ (3.17 g, 41.6mmol) in THF (150 mL) was added sodium hydride (1.997 g, 83 mmol) at 0°C. After 30 min at 0° C., the reaction was warmed to room temperatureand stirred for 1 h, then refluxed for 4 h. The reaction was cooled toroom temperature, added iodomethane (16.23 g, 104 mmol), and refluxedfor another 12 h. The reaction was cooled and extracted with ethylacetate. The organic extracts were concentrated under reduced pressure.The residue was diluted with ethanol (200 mL), added hydrazine (1.334 g,41.6 mmol), and refluxed for 4 h. After cooling, the mixture wasconcentrated under reduced pressure and extracted with ethyl acetate.The organic extracts were dried over MgSO₄ and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound (6.02 g). LCMS m/z=191.37[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31 (s, 3H), 6.21 (s, 1H),7.38-7.56 (m, 5H), 12.2 (s, 1H).

Step B: Preparation of 4-Iodo-5-(methylthio)-3-phenyl-1H-pyrazole

To a solution of 5-(methylthio)-3-phenyl-1H-pyrazole (1.5 g, 7.88 mmol)in THF (20 mL) and water (20 mL), were added sodium iodide (1.182 g,7.88 mmol), iodine (3.00 g, 11.83 mmol), and K₂CO₃ (1.634 g, 11.83 mmol)at room temperature. The reaction was warmed to 100° C. and stirred for2 h. The reaction was quenched with 2.0 M aqueous sodium thiosulfite andconcentrated under reduced pressure. The mixture was extracted withethyl acetate and washed with NaHCO₃ solution. The organic extracts weredried over MgSO₄ and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to give the titlecompound (2.35 g). LCMS m/z=317.02 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 2.43 (s, 3H), 7.43-7.79 (m, 5H), 13.5 (s, 1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Iodo-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 5-(methylthio)-3,4-diphenyl-1H-pyrazole (100 mg, 0.375mmol) in DMF (3 mL), was added sodium hydride (9.01 mg, 0.375 mmol) atroom temperature. After stirring for 10 min, a solution of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (154 mg, 0.375mmol) in DMF (1 mL) was added at room temperature. The reaction washeated to 45° C. and stirred for 8 h. The reaction was poured into H₂Oand extracted with ethyl acetate. The organic extract was dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound (2.98 g).LCMS m/z=557.48 [M+H]⁺.

Step D: Preparation of2-(((1s,4s)-4-((4-(5-Cyano-2-fluorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((4-iodo-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(110 mg, 0.198 mmol) in dioxane (2 mL), were added5-cyano-2-fluorophenylboronic acid (32.6 mg, 0.198 mmol),Pd(PPh₃)₄(11.42 mg, 9.88 μmol), and K₂CO₃ (54.6 mg, 0.395 mmol) at roomtemperature. The reaction was heated under microwave irradiation for 1.5h at 150° C. The mixture was filtered and concentrated under reducedpressure. The residue was treated with 4.0 M HCl (5 mL) for 10 h. Themixture was concentrated under reduced pressure and purified by HPLC togive the title compound (68 mg). LCMS m/z=494.5 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.31-1.40 (m, 8H), 1.60-1.78 (m, 1H), 2.18-2.20 (m, 1H),2.38 (s, 3H), 3.51 (d, J=7.0 Hz, 2H), 3.79 (s, 2H), 4.19 (d, J=7.5 Hz,2H), 7.21-7.34 (m, 5H), 7.80-7.41 (m, 3H).

Example 1.5: Preparation of2-(((1s,4s)-4-((4-(Furan-2-yl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 109)

To a solution of tert-butyl2-(((1s,4s)-4-((4-iodo-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.270 mmol) in dioxane (1 mL), was added furan-2-yl boronicacid (31.23 mg, 0.270 mmol) followed by Pd(PPh₃)₄(15.57 mg, 0.013 mmol)and K₂CO₃ (74.5 mg, 0.539 mmol) at room temperature. The reaction washeated under microwave at 120° C. for 1.5 h. The mixture was extractedwith ethyl acetate and the organic extract was concentrated underreduced pressure. The residue was treated with 4.0 M HCl (3.37 mL, 13.48mmol) for 5 h. The reaction was concentrated under reduced pressure andpurified by HPLC to give the title compound (88 mg). LCMS m/z=441.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24-1.39 (m, 8H), 1.64-1.80 (m,1H), 2.12-2.17 (m, 1H), 2.34 (s, 3H), 3.49 (d, J=7.0 Hz, 2H), 3.78 (s,2H), 4.19 (d, J=7.5 Hz, 2H), 7.31-7.45 (m, 8H).

Example 1.6: Preparation of2-(((1s,4s)-4-((4-(5-Fluoropyridin-3-yl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 135)

To a solution of tert-butyl2-(((1s,4s)-4-((4-iodo-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(500 mg, 0.898 mmol) in dioxane (5 mL) was added5-fluoropyridin-3-ylboronic acid (127 mg, 0.898 mmol) followed byPd(PPh₃)₄(51.9 mg, 0.045 mmol) and K₂CO₃ (248 mg, 1.797 mmol) at roomtemperature. The reaction was heated under microwave irradiation at 120°C. for 1.5 h. The reaction mixture was extracted with ethyl acetate andthe organic extracts were concentrated under reduced pressure. Theresidue was treated with 4.0 M HCl (11.23 mL, 44.9 mmol) in dioxane for5 h. The mixture was concentrated under reduced pressure and the residuewas purified by HPLC to give the title compound as a solid. The solidwas dissolved in acetonitrile (1 mL) and water (2 mL) and added 1.0 eq.of NaOH in H₂O (1 mL). The mixture was concentrated under reducedpressure to give the sodium salt of the title compound (210 mg). LCMSm/z=470.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.58 (m, 8H),1.74-1.80 (m, 1H), 2.20 (s, 3H), 2.21-2.31 (m, 1H), 3.31 (d, J=7.0 Hz,2H), 3.73 (s, 2H), 4.32 (d, J=7.5 Hz, 2H), 6.65-7.40 (m, 5H), 7.76-7.70(m, 1H), 8.34 (s, 1H), 8.55 (s, 1H).

Example 1.7: Preparation of2-(((1s,4s)-4-((5-(Methylthio)-4-(5-methylthiophen-2-yl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 111)

To a solution of tert-butyl2-(((1s,4s)-4-((4-iodo-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(500 mg, 0.981 mmol) in dioxane (5 mL) was added5-methylthiophen-2-ylboronic acid (139 mg, 0.981 mmol) followed byPd(PPh₃)₄(56.7 mg, 0.049 mmol) and K₂CO₃ (271 mg, 1.963 mmol) at roomtemperature. The reaction was heated under microwave at 120° C. for 1.5h. The mixture was extracted with ethyl acetate and concentrated underreduced pressure. The residue was treated with HCl (4.0 M in dioxane)for 5 h. The mixture was concentrated under reduced pressure and theresidue was purified by HPLC to give the title compound as a solid. Thesolid was dissolved in acetonitrile (1 mL) and water (2 mL) and added1.0 eq. of NaOH in H₂O (1 mL). The mixture was concentrated underreduced pressure to give the sodium salt of the title compound (158 mg).LCMS m/z=470.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.49 (m,8H), 1.63-1.79 (m, 1H), 2.08-2.13 (m, 1H), 2.15 (s, 3H), 2.35 (s, 3H),3.54 (d, J=7.0 Hz, 2H), 3.88 (s, 2H), 4.20 (d, J=7.5 Hz, 2H), 7.23-7.48(m, 7H).

Example 1.8: Preparation of2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 14)

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(1.5 g, 3.14 mmol) in dioxane (12 mL) was added 3-methoxyphenylboronicacid (0.477 g, 3.14 mmol) followed by Pd(PPh₃)₄(0.182 g, 0.157 mmol) andK₂CO₃ (0.868 g, 6.28 mmol) at room temperature. The reaction was heatedunder microwave irradiation at 150° C. for 1 h. The reaction wasextracted with ethyl acetate and the organic extracts were concentratedunder reduced pressure. The residue was treated with HCl (4.0 M indioxane) for 5 h. The mixture was concentrated under reduced pressureand the residue was purified by HPLC to give the title compound as thefree acid. The free acid was treated with NaOH in 30% acetonitrile/H₂Oand the mixture was concentrated under reduced pressure to give thesodium salt of the title compound (0.687 g). LCMS m/z=449.2 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.52 (m, 8H), 1.71-1.83 (m, 1H),2.01-2.11 (m, 1H), 2.20 (s, 3H), 3.41 (d, J=7.0 Hz, 2H), 3.78 (s, 2H),3.85 (s, 3H), 4.13 (d, J=7.5 Hz, 2H), 6.65-7.40 (m, 9H).

Example 1.9: Preparation of2-(((1R,4s)-4-((5-((S)-3,4-Dihydroxybutyl)-4-(3-hydroxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 161) Step A: Preparation of 1-Phenylhept-6-ene-1,3-dione

To a solution of 1-phenylbutane-1,3-dione (5 g, 30.8 mmol) in THF (50mL) was added sodium hydride (0.740 g, 30.8 mmol) at 0° C. After warmingand stirring at room temperature for 30 min, LDA, which was made byadding BuLi (1.975 g, 30.8 mmol) to a solution of diisopropylamine (4.39mL, 30.8 mmol) in THF (50 mL) at −45° C., was added at 0° C. Afterstirring for 30 min at the same temperature, 3-bromoprop-1-ene (3.73 g,30.8 mmol) was added at 0° C. After stirring for 1 h, the reaction wasquenched with 1.0 M HCl and extracted with ethyl acetate. The organicextract was dried over MgSO₄ and concentrated under reduced pressure togive the title compound without further purification. LCMS m/z=203.19[M+H]⁺.

Step B: Preparation of 5-(But-3-enyl)-3-phenyl-1H-pyrazole

To a solution of 1-phenylhept-6-ene-1,3-dione (3 g, 14.83 mmol) inethanol (50 mL) was added hydrazine hydrate (2.228 g, 44.5 mmol) at roomtemperature. The reaction was refluxed for 10 h, cooled to roomtemperature and concentrated under reduced pressure. The residue wasextracted with ethyl acetate. The organic extract was dried over MgSO₄and concentrated under reduced pressure to give the title compoundwithout further purification. LCMS m/z=199.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.65-2.78 (m, 2H), 4.01-4.12 (m, 2H), 4.83-4.95 (m, 2H),5.82-5.93 (m, 1H), 6.42 (s, 1H), 7.23-7.82 (m, 5H), 12.6 (s, 1H).

Step C: Preparation of (S)-4-(3-Phenyl-1H-pyrazol-5-yl)butane-1,2-diol

To a solution of 5-(but-3-enyl)-3-phenyl-1H-pyrazole (1 g, 5.04 mmol) inH₂O (25 mL), and isopropanol (25 mL) was added AD-mix-β (5 g, 5.04 mmol)at room temperature. The reaction was stirred for 48 h, quenched withNa₂SO₃ and extracted with ethyl acetate. The organic extract was driedover MgSO₄ and concentrated under reduced pressure to give the titlecompound (1.02 g) without further purification. LCMS m/z=232.9 [M+H]⁺.

Step D: Preparation of(S)-5-(2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazole

To a solution of (S)-4-(3-phenyl-1H-pyrazol-5-yl)butane-1,2-diol (2.5 g,10.76 mmol) in acetone (50 mL) were added 2,2-dimethoxypropane (11.21 g,108 mmol) and p-toluenesulfonic acid (0.185 g, 1.076 mmol) at roomtemperature. After stirring for 3 h, the reaction was concentrated underreduced pressure. The residue was extracted with ethyl acetate. Theorganic extract was dried over MgSO₄ and concentrated under reducedpressure to give the title compound (2.70 g) without furtherpurification. LCMS m/z=273.0 [M+H]⁺.

Step E: Preparation of(S)-4-Bromo-5-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazole

To a solution of(S)-5-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazole(1.1 g, 4.04 mmol) and MP-carbonate in CH₂Cl₂ (50 mL) was added bromine(0.645 g, 4.04 mmol) dropwise at 0° C. After stirring for 1 h,MP-carbonate (12.4 g, 40.4 mmol) was filtered off and washed withCH₂Cl₂. The combined filtrate was poured into water, extracted withCH₂Cl₂, dried over MgSO₄, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to give thetitle compound as an oil (1.129 g). LCMS m/z=351.1 [M+H]⁺.

Step F: Preparation of tert-Butyl2-(((1R,4s)-4-((4-Bromo-5-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of(S)-4-bromo-5-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazole(1.23 g, 3.50 mmol) in DMF (10 mL) was added sodium hydride (0.084 g,3.50 mmol) at room temperature. After stirring for 30 min, tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (1.44 g, 3.50mmol) was added and the reaction was heated to 45° C. After stirring for12 h at the same temperature, the reaction was poured into H₂O andextracted with ethyl acetate. The organic extract was dried over MgSO₄and concentrated under reduced pressure to give the title compoundwithout further purification. LCMS m/z=592.1 [M+H]⁺.

Step G: Preparation of2-(((1R,4s)-4-((5-((S)-3,4-Dihydroxybutyl)-4-(3-hydroxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.254 mmol) in dioxane (1 mL) was added 3-hydroxyphenylboronicacid (35.0 mg, 0.254 mmol) followed by Pd(PPh₃)₄(14.65 mg, 0.013 mmol)and K₂CO₃ (70.1 mg, 0.507 mmol) at room temperature. The reaction washeated under microwave at 120° C. for 1.5 h. The reaction was extractedwith ethyl acetate and concentrated under reduced pressure. The residuewas treated with HCl (4.0 M in dioxane) for 5 h. The mixture wasconcentrated under reduced pressure and purified by HPLC to give thetitle compound (59 mg). LCMS m/z=509.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆)ppm 1.20-1.62 (m, 12H), 1.75-1.80 (m, 1H), 2.10-2.15 (m, 1H), 2.45-2.70(m, 1H), 3.14-3.20 (m, 2H), 3.39 (d, J=7.0 Hz, 2H), 3.83 (s, 2H), 4.05(d, J=7.5 Hz, 2H), 6.50-7.35 (m, 9H).

Example 1.10: Preparation of2-(((1s,4s)-4-((5-(Cyanomethylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 184) Step A: Preparation of3,4-Diphenyl-1H-pyrazole-5(4H)-thione

To a solution of 1,2-diphenylethanone (10 g, 51.0 mmol) in acetone (250mL) were added K₂CO₃ (21.1 g, 153 mmol), CS₂ (11.62 g, 153 mmol), anddibromomethane (26.5 g, 153 mmol) at room temperature. The reaction wasstirred for 48 h at 40° C. The reaction mixture was extracted with ethylacetate, dried over MgSO₄, and concentrated under reduced pressure. Theresulting residue was diluted with ethanol (125 mL) and hydrazinehydrate (2.55 g, 50.9 mmol) was added at room temperature. The reactionwas refluxed for 4 h, cooled, and concentrated under reduced pressure.The residue was triturated with isopropanol and dried under reducedpressure to give the title compound as a white solid (8.25 g). LCMSm/z=253.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.14 (bs, 1H),7.34-7.54 (m, 10H), 12.5 (s, 1H).

Step B: Preparation of 2-(3,4-Diphenyl-1H-pyrazol-5-ylthio)acetonitrile

To a solution of 3,4-diphenyl-1H-pyrazole-5(4H)-thione (0.5 g, 1.981mmol) in DMF (5 mL), were added 2-bromoacetonitrile (0.238 g, 1.981mmol) and K₂CO₃ (0.274 g, 1.981 mmol) at room temperature. Afterstirring at the same temperature for 1 h, the reaction was extractedwith ethyl acetate, which was dried over MgSO₄ and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound (0.38 g). LCMS m/z=292.0[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.20 (s, 2H), 7.35-7.45 (m,10OH), 13.7 (s, 1H).

Step C: Preparation of2-(((1s,4s)-4-((5-(Cyanomethylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of 2-(3,4-diphenyl-1H-pyrazol-5-ylthio)acetonitrile (330mg, 1.133 mmol) in DMF (2 mL) was added sodium hydride (27.2 mg, 1.133mmol) at 0° C. After stirring for 10 min, tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (467 mg, 1.133mmol) was added. The reaction was warmed to 40° C. and stirred for 12 h.The reaction mixture was extracted with ethyl acetate. The organicextract was concentrated under reduced pressure and the residue wastreated with 4.0 M HCl for 8 h. The mixture was concentrated underreduced pressure and the residue was purified by HPLC to give the titlecompound (92 mg). LCMS m/z=476.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.31-1.53 (m, 8H), 1.63 (m, 1H), 2.15 (m, 1H), 3.32 (d, J=7.0 Hz, 2H),3.63 (s, 2H), 3.73 (s, 2H), 4.25 (d, J=7.5 Hz, 2H), 7.21-7.35 (m, 10H).

Example 1.11: Preparation of2-(((1s,4s)-4-((5-(Methylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 76) Step A: Preparation5-(Methylthio)-3,4-diphenyl-1H-pyrazole

To a solution of 1,2-diphenylethanone (5 g, 25.5 mmol) in anhydrous THF(10 mL) was added a solution of 1.0 M KO-t-Bu in THF (108 mL). Thereaction was stirred for 15 min at room temperature, then CS₂ (2.09 g,27.5 mmol) was added. After 10 min, iodomethane (7.96 g, 56.1 mmol) wasadded and the reaction was stirred for 4 h. The reaction was washed withsaturated NaHCO₃ solution and dried over MgSO₄. The filtrate wasconcentrated under reduced pressure and the residue was triturated with10% ethyl acetate. The solid was suspended in ethanol and hydrazinehydrate (5.10 g, 102 mmol) was added at room temperature. The reactionwas refluxed for 4 h. The reaction mixture was concentrated underreduced pressure and the residue was triturated with ethylacetate/hexane to give the title compound as a white solid (5.2 g). LCMSm/z=267.27 [M+H]⁺.

Step B: Preparation of2-((1s,4s)-4-((5-(Methylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of 5-(methylthio)-3,4-diphenyl-1H-pyrazole (100 mg, 0.375mmol) in DMF (3 mL) was added sodium hydride (9.01 mg, 0.375 mmol) atroom temperature. After stirring for 10 min, a solution of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (155 mg, 0.375mmol) in DMF (1 mL) was added. The reaction was heated to 45° C. andstirred for 8 h. The reaction mixture was poured into H₂O and extractedwith ethyl acetate. The organic extract was dried over MgSO₄ andconcentrated under reduced pressure. The residue was treated with HCl(4.0 M in dioxane) overnight. The mixture was concentrated under reducedpressure and the residue was purified by HPLC to give the title compound(98 mg). LCMS m/z=451.47 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.33-1.55 (m, 8H), 2.12 (s, 3H) 1.69-1.81 (m, 1H), 2.14-2.26 (m, 1H),3.39 (d, J=7.0 Hz, 2H), 3.80 (s, 2H), 4.28 (d, J=7.5 Hz, 2H), 7.21-7.43(m, 10H).

Example 1.12: Preparation of2-(((1s,4s)-4-((4-(4-Chlorophenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 21) Step A: Preparation of 5-Methyl-3-phenyl-1H-pyrazole

To a solution of acetophenone (10 g, 83 mmol) in anhydrous toluene (10mL) was added LiHMDS (1.0 M in THF, 83 mL, 83 mmol) via syringe at 0° C.under argon. After 5 min, acetyl chloride (6.53 g, 83 mmol) was added inone portion via syringe. The ice bath was removed and glacial AcOH (5mL), EtOH (50 mL), and hydrazine hydrate (12.50 g, 250 mmol) were added.The mixture was refluxed for 2 h. After cooled to room temperature, thereaction was neutralized to pH 7 by adding 1.0 M NaOH solution. Themixture was extracted with EtOAc, washed with brine, dried over MgSO₄,and concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale yellow oil (12.05g). LCMS m/z=159.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H),6.42 (s, 1H), 7.20-7.44 (m, 3H), 7.67-7.82 (m, 2H), 12.53 (bs, 1H).

Step B: Preparation of 4-Bromo-5-methyl-3-phenyl-1H-pyrazole

To a solution of 5-methyl-3-phenyl-1H-pyrazole (8.0 g, 50.6 mmol) indichloromethane (150 mL) was added bromine (8.08 g, 50.6 mmol) dropwiseat 0° C. The reaction was stirred at that temperature for 30 min andcontinued at room temperature for 2 h. After the reaction was quenchedwith an aqueous solution of Na₂SO₃ (10% w/w, 10 mL), the organic solventwas removed and the aqueous mixture was extracted with EtOAc, washedwith brine, dried over MgSO₄, and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound as ayellow oil (9.5 g). LCMS m/z=236.9 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δppm 2.26 (s, 3H), 7.30-7.57 (m, 5H), 13.12 (s, 1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 4-bromo-5-methyl-3-phenyl-1H-pyrazole (2.0 g, 8.44mmol) in DMF (5 mL) was added sodium hydride (0.202 g, 8.44 mmol) inportions at 0° C. The reaction was stirred at 0° C. for 1 h andtert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(3.48 g, 8.44 mmol) was added. The reaction was heated to 42° C.,stirred for 16 h, and quenched with H₂O (2 mL). The mixture wasextracted with ethyl acetate, dried over MgSO₄ and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound as a colorless liquid (3.05g). LCMS m/z=477.3 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26-1.50 (m,8H), 1.43 (s, 9H), 1.66-1.78 (m, 1H), 1.97-2.09 (m, 1H), 2.30 (s, 3H),3.39 (d, J=6.82 Hz, 2H), 3.94 (s, 2H), 4.06 (d, J=7.58 Hz, 2H),7.30-7.50 (m, 3H), 7.74-7.85 (m, 2H).

Step D: Preparation of2-(((1s,4s)-4-((4-(4-Chlorophenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(100 mg, 0.19 mmol) in dioxane (3 mL) were added 4-chlorophenylboronicacid (29.8 mg, 0.19 mmol), tetrakis(triphenylphosphine)palladium (22 mg,0.019 mmol), and K₂CO₃ (2 M aqueous, 0.2 mL). The reaction was heated to150° C. under microwave irradiation for 4 h. The reaction mixture wasfiltered and the filtrate was concentrated. The residue was treated withHCl (4 M in dioxane, 5 mL) at room temperature for 10 h. The mixture wasconcentrated and the residue was purified by HPLC to give the titlecompound (13.5 mg). LCMS m/z=453.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.01-1.19 (m, 4H), 1.21-1.36 (m, 4H), 1.54-1.66 (m, 1H), 1.86-1.98(m, 1H), 2.22 (s, 3H), 3.19 (d, J=6.95 Hz, 2H), 3.89 (d, J=7.45 Hz, 2H),3.91 (s, 2H), 7.04-7.11 (m, 2H), 7.21-7.31 (m, 5H), 7.39-7.47 (m, 2H).

Example 1.13: Preparation of2-(((1s,4s)-4-((5-(Ethylthio)-4-(2-fluoro-3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 90)

From 5-(ethylthio)-3-phenyl-1H-pyrazole, using a similar method to theone described in Example 1.4, the title compound was obtained. LCMSm/z=513.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.96 (t, J=7.33 Hz, 3H),1.30-1.52 (m, 8H), 1.68-1.80 (m, 1H), 2.14-2.26 (m, 1H), 2.53 (q, J=7.33Hz, 2H), 3.37 (d, J=6.95 Hz, 2H), 3.68 (s, 2H), 3.84 (s, 3H), 4.28 (d,J=7.58 Hz, 2H), 6.76-6.94 (m, 2H), 7.13-7.40 (m, 6H).

Example 1.14: Preparation of2-(((1s,4s)-4-((5-Ethyl-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 99) Step A: Preparation of 5-Ethyl-3-phenyl-1H-pyrazole

To a solution of acetophenone (10 g, 83 mmol) in anhydrous toluene (10mL) added LiHMDS (85.0 mL, 1.0 M in THF, 85.0 mmol) via syringe at 0° C.under argon. After 5 min, propionyl chloride (7.70 g, 83 mmol) was addedin one portion via syringe. The ice bath was removed after 10 min andAcOH (2 mL), EtOH (50 mL), and hydrazine hydrate (8.35 g, 116 mmol) wereadded. The mixture was refluxed for 2 h. The resulting solution wasadded to 1.0 M NaOH solution, extracted with EtOAc, washed with brine,dried over MgSO₄, and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a clearyellowish liquid (12.05 g). LCMS m/z=173.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.23 (t, J=7.58 Hz, 3H), 2.64 (q, J=7.07 Hz, 2H), 6.46(s, 1H), 7.20-7.52 (m, 3H), 7.77 (d, J=6.32 Hz, 2H), 12.55 (s, 1H).

Step B: Preparation of 4-Bromo-5-ethyl-3-phenyl-1H-pyrazole

To a solution of 5-ethyl-3-phenyl-1H-pyrazole (10.0 g, 58.1 mmol) in DCM(150 mL) was added dropwise bromine (9.28 g, 58.1 mmol) at 0° C. Thereaction was stirred at that temperature for 30 min and continued for 2h at room temperature and then quenched with aqueous Na₂SO₃ solution(10% w/w, 10 mL). DCM was removed and the residue was extracted withEtOAc, washed with brine, dried over MgSO₄, and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a yellow liquid (9.5 g). LCMS m/z=250.9 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.22 (t, J=7.58 Hz, 3H), 2.66 (q, J=7.58 Hz,2H), 7.40-7.56 (m, 3H), 7.82 (d, J=7.58 Hz, 2H), 13.15 (s, 1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 4-bromo-5-ethyl-3-phenyl-1H-pyrazole (3.0 g, 11.95mmol) in DMF (5 mL) was added sodium hydride (0.287 g, 11.95 mmol)followed by tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (4.93 g, 11.95mmol). The reaction was heated at 45° C. overnight, quenched with water(2 mL), and the mixture was extracted with EtOAc. The organic phase waswashed with brine, dried over MgSO₄, and concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a clear liquid (4.5 g). LCMS m/z=491.2 [M+H]J; ¹H NMR (400 MHz,CDCl₃) δ ppm 1.25 (t, J=7.20 Hz, 3H), 1.31-1.43 (m, 4H), 1.49 (s, 9H),1.51-1.60 (m, 4H), 1.76-1.90 (m, 1H), 2.12-2.24 (m, 1H), 2.72 (q, J=7.75Hz, 2H), 3.46 (d, J=6.82 Hz, 2H), 3.92 (s, 2H), 4.01 (d, J=7.58 Hz, 2H),7.31-7.43 (m, 3H), 7.86 (d, J=7.33 Hz, 2H).

Step D: Preparation of2-(((1s,4s)-4-((5-Ethyl-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

A mixture of 3-methoxyphenylboronic acid (0.141 g, 0.929 mmol),tert-butyl2-(((1s,4s)-4-((5-ethyl-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(0.5 g, 0.929 mmol), tetrakis(triphenylphosphine)palladium (0.107 g,0.093 mmol), K₂CO₃ (2 M aqueous, 0.5 mL) and dioxane (10 mL) was heatedto 150° C. under microwave for 4 h. The reaction mixture was filteredand the filtrate was concentrated. The residue was treated with HCl (4 Min dioxane, 5 mL) at room temperature for 10 h. The mixture wasconcentrated and the residue was purified by HPLC to give the titlecompound (0.135 g). LCMS m/z=463.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.04 (t, J=7.45 Hz, 3H), 1.35-1.55 (m, 8H), 1.71-1.83 (m, 1H),2.06-2.18 (m, 1H), 2.60 (q, J=7.58 Hz, 2H), 3.40 (d, J=6.95 Hz, 2H),3.70 (s, 3H), 3.72 (s, 2H), 4.02 (d, J=7.45 Hz, 2H), 6.69-6.78 (m, 2H),6.85-6.91 (m, 1H), 7.15-7.36 (m, 6H).

Example 1.15: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 113) Step A: Preparation of5-Isopropyl-3-phenyl-1H-pyrazole

To a solution of acetophenone (1.21 g, 10.07 mmol) in dry toluene (5 mL)was added LiHMDS (11.0 mL, 1.0 M in THF, 11.0 mmol) via syringe at 0° C.under argon. After 5 min, isobutyryl chloride (1.073 g, 10.07 mmol) wasadded in one portion via syringe. The ice bath was removed and AcOH (2mL), EtOH (50 mL) and THF (5 mL) were added to form a homogeneousmixture. Hydrazine hydrate (2 mL, 10.07 mmol) was added and the reactionwas refluxed for 2 h.

The reaction was cooled to room temperature and concentrated. Theresidue was extracted with EtOAc, washed with brine, dried over MgSO₄,and concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless oil (0.70 g).LCMS m/z=187.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.33 (d, J=6.82 Hz,6H), 2.94-3.13 (m, 1H), 6.38 (s, 1H), 7.17-7.45 (m, 5H), 10.14 (bs, 1H).

Step B: Preparation of 4-Iodo-5-isopropyl-3-phenyl-1H-pyrazole

To a solution of 5-isopropyl-3-phenyl-1H-pyrazole (0.64 g, 3.44 mmol) inTHF (20 mL) and water (20.00 mL) were added sodium iodide (0.515 g, 3.44mmol), iodine (1.308 g, 5.15 mmol), and potassium carbonate (0.712 g,5.15 mmol) at room temperature. The reaction was refluxed for 2 h,cooled to room temperature and quenched with 10% aqueous Na₂SO₃. Theorganic solvent was removed under reduced pressure and the aqueousresidue was extracted with EtOAc. The organic extract was washed withNaHCO₃ solution, brine, dried over MgSO₄, and concentrated. The residuewas purified by silica gel column chromatography to give the titlecompound as a clear liquid (0.42 g). LCMS m/z=313.2 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ ppm 1.17 (d, J=7.07 Hz, 6H), 3.02 (septet, J=7.07 Hz, 1H),7.23-7.32 (m, 3H), 7.60-7.67 (m, 2H), 11.81 (bs, 1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Iodo-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 4-iodo-5-isopropyl-3-phenyl-1H-pyrazole (0.35 g, 1.121mmol) in DMF (5 mL) was added sodium hydride (0.027 g, 1.121 mmol) atroom temperature. The reaction was stirred at room temperature for 1 hand tert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(0.463 g, 1.121 mmol) was added. The reaction was heated at 50° C. for16 h, cooled to room temperature, and quenched with water (2 mL). Themixture was extracted with EtOAc. The organic extract was dried overMgSO₄ and concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a clear liquid (0.52 g).LCMS m/z=553.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.99-1.20 (m, 4H),1.25-1.42 (m, 4H), 1.46 (d, J=7.20 Hz, 6H), 1.48 (s, 9H), 1.82-1.94 (m,1H), 2.07-2.19 (m, 1H), 3.16-3.28 (m, 1H), 3.45 (d, J=7.07 Hz, 2H), 3.95(s, 2H), 4.07 (d, J=7.71 Hz, 2H), 7.30-7.46 (m, 3H), 7.63-7.79 (m, 2H).

Step C: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

A mixture of 3-fluorophenylboronic acid (25.3 mg, 0.181 mmol),tert-butyl2-(((1s,4s)-4-((4-iodo-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(100 mg, 0.181 mmol), tetrakis(triphenylphosphine)palladium (10.0 mg,0.009 mmol), K₂CO₃ (2 M aqueous, 0.2 mL) and dioxane (4 mL) was heatedto 150° C. under microwave irradiation for 4 h. The mixture was filteredand the filtrate was concentrated. The residue was treated with HCl (4 Min dioxane, 5 mL) at room temperature for 10 h. The mixture wasconcentrated and the residue was purified by HPLC to give the titlecompound (15.5 mg). LCMS m/z=465.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.10 (d, J=7.07 Hz, 6H), 1.34-1.59 (m, 8H), 1.72-1.85 (m, 1H),2.06-2.19 (m, 1H), 3.09-3.22 (m, 1H), 3.44 (d, J=7.07 Hz, 2H), 4.00 (s,2H), 4.08 (d, J=7.58 Hz, 2H), 7.00-7.10 (m, 2H), 7.14-7.28 (m, 5H),7.37-7.46 (m, 2H).

Example 1.16: Preparation of2-(((1s,4s)-4-((3-Cyclopropyl-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 121) Step A: Preparation of5-Cyclopropyl-3-phenyl-1H-pyrazole

To a solution of acetophenone (5.0 g, 41.6 mmol) in dry toluene (5 mL)was added LiHMDS (42.0 mL, 1.0 M in THF, 42.0 mmol) via syringe at 0° C.under argon. After 5 min, cyclopropanecarbonyl chloride (4.35 g, 41.6mmol) was added in one portion via syringe. The ice bath was removed andAcOH (2 mL), EtOH (50 mL), and hydrazine hydrate (10 mL, 64% aqueous,127.8 mmol) was added. The mixture was refluxed for 30 min, cooled toroom temperature, and concentrated. The residue was extracted withEtOAc, washed with brine, dried over MgSO₄, and purified by silica gelcolumn chromatography to give the title compound as a colorless oil (4.5g). LCMS m/z=184.7 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.71-0.80 (m,2H), 0.89-1.00 (m, 2H), 1.81-1.98 (m, 1H), 6.22 (s, 1H), 7.11-7.56 (m,5H), 10.50 (bs, 1H).

Step B: Preparation of 5-Cyclopropyl-4-iodo-3-phenyl-1H-pyrazole

To a solution of 5-cyclopropyl-3-phenyl-1H-pyrazole (3.0 g, 16.28 mmol)in THF (20 mL) and water (20 mL) were added sodium iodide (2.441 g,16.28 mmol), iodine (6.20 g, 24.43 mmol), and potassium carbonate (3.38g, 24.43 mmol) at room temperature. The reaction was refluxed for 2 h(100° C.). The reaction was cooled to room temperature and quenched with10% aqueous Na₂SO₃. The organic solvent was removed under reducedpressure and the aqueous phase was extracted with EtOAc, washed withNaHCO₃ solution, brine, dried over MgSO₄, and concentrated. The residuewas purified by silica gel column chromatography (2.7 g). LCMS m/z=310.8[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.75-0.81 (m, 2H), 0.83-0.88 (m,2H), 2.46-2.56 (m, 1H), 7.33-7.47 (m, 3H), 7.62-7.71 (m, 2H), 12.91 (s,1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((3-Cyclopropyl-4-iodo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

A solution of 5-cyclopropyl-4-iodo-3-phenyl-1H-pyrazole (3.5 g, 11.29mmol) in DMF (5 mL) was treated with sodium hydride (0.271 g, 11.29mmol) at room temperature for 1 h, then tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (4.66 g, 11.29mmol) was added. The reaction mixture was heated to 50° C. for 16 h andquenched with water (2 mL). The mixture was extracted by EtOAc, driedover MgSO₄, and concentrated. The residue was purified by silica gelcolumn chromatography to give the title compound as a colorless oil (4.5g). LCMS m/z=551.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.04-1.19 (m,4H), 1.33-1.44 (m, 4H), 1.46 (s, 9H), 1.47 (d, J=8.08 Hz, 4H), 1.67-1.77(m, 1H), 1.85-1.91 (m, 1H), 1.90-1.99 (m, 1f), 3.25 (d, J=7.07 Hz, 2H),3.87 (s, 2H), 3.91 (d, J=7.58 Hz, 2H), 7.28-7.54 (m, 5H).

Step D: Preparation of2-(((1s,4s)-4-((3-Cyclopropyl-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

A mixture of phenylboronic acid (25.3 mg, 0.181 mmol), tert-butyl2-(((1s,4s)-4-((3-cyclopropyl-4-iodo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(100 mg, 0.181 mmol), tetrakis(triphenylphosphine)palladium (10.0 mg,0.009 mmol), K₂CO₃ (2 M aqueous, 0.2 mL) and dioxane (4 mL) was heatedto 150° C. under microwave irradiation for 4 h. The mixture was filteredand the filtrate was concentrated. The residue was treated with HCl (4 Min dioxane, 5 mL) at room temperature for 10 h. The mixture wasconcentrated and the residue was purified by HPLC to give the titlecompound (23.5 mg). LCMS m/z=445.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.32-1.55 (m, 8H), 1.71-1.82 (m, 1H), 2.04-2.17 (m, 1H), 2.28 (s,3H), 2.93 (t, J=6.82 Hz, 2H), 3.16 (s, 3H), 3.40 (t, J=6.63 Hz, 2H),3.41 (d, J=6.69 Hz, 2H), 3.87 (s, 2H), 4.07 (d, J=7.45 Hz, 2H),6.87-6.98 (m, 2H), 7.07-7.13 (m, 2H), 7.16-7.31 (m, 5H).

Example 1.17: Preparation of2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 143) Step A: Preparation of3-Iodo-5-methyl-4-phenyl-1H-pyrazole

To a solution of 5-methyl-4-phenyl-1H-pyrazole (5.0 g, 31.6 mmol) in THF(40 mL) and water (40 mL) were added sodium iodide (4.74 g, 31.6 mmol),iodine (12.03 g, 47.4 mmol), and K₂CO₃ (4.37 g, 31.6 mmol) at roomtemperature. The reaction was refluxed for 2 h and then quenched withaqueous Na₂SO₃ (10%). The mixture was extracted with ethyl acetate,dried over MgSO₄, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to give the titlecompound as a colorless oil (2.5 g). LCMS m/z=284.7 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.26 (s, 3H), 7.24-7.54 (m, 5H), 13.13 (s, 1H).

Step B: Preparation of tert-Butyl2-(((1s,4s)-4-((3-Iodo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

A solution of 3-iodo-5-methyl-4-phenyl-1H-pyrazole (2.0 g, 7.04 mmol) inDMF (5 mL) was treated with sodium hydride (0.169 g, 7.04 mmol) at roomtemperature for 1 h, then tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (2.9 g, 7.04mmol) was added. The reaction mixture was heated to 50° C. for 16 hbefore it was quenched by addition of water (2 mL). The mixture wasextracted with EtOAc, dried over MgSO₄ and concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a colorless oil (1.5 g).

LCMS m/z=525.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27-1.52 (m,8H), 1.44 (s, 9H), 1.68-1.80 (m, 1H), 1.95-2.07 (m, 1H), 1.99 (s, 3H),3.40 (d, J=6.82 Hz, 2H), 3.96 (s, 2H), 4.03 (d, J=7.33 Hz, 2H),7.28-7.46 (m, 5H).

Step C: Preparation of2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

A solution of 2-fluoro-4-methylphenylboronic acid (29.4 mg, 0.191 mmol),tert-butyl2-(((1s,4s)-4-((3-iodo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(100 mg, 0.191 mmol), tetrakis(triphenylphosphine)palladium (22.03 mg,0.019 mmol), and K₂CO₃ (2 M aqueous, 0.5 mL) in dioxane (3 mL) washeated to 150° C. under microwave irradiation for 2 h. The mixture wasfiltered and the filtrate was concentrated. The residue was treated withHCl (4 M in dioxane, 3 mL) at room temperature for 16 h. The mixture wasconcentrated and the residue was purified by HPLC (Varian ProStar; PrepColumn: Phenomenex™ 00G-4253-V0, Luna™ C18(2), 10 μm, 100 Å, 250×50 mmID; Eluent: 40-65% ACN/H₂O with 0.1% TFA over 15 min, and then 65%ACN/H₂O with 0.1% FTA isocratic over 50 min) to give the title compound(retention time: 41 min, 25.0 mg). LCMS m/z=451.1 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.32-1.52 (m, 8H), 1.69-1.79 (m, 1H), 2.02-2.13 (m,1H), 2.28 (s, 3H), 2.30 (s, 3H), 3.39 (d, J=6.95 Hz, 2H), 3.99 (s, 2H),4.06 (d, J=7.45 Hz, 2H), 6.91 (d, J=11 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H),7.05 (m, 1H), 7.07 (m, 1H), 7.15-7.31 (m, 4H). A compound eluting at 37min under the same HPLC conditions was collected and identified as theregioisomer of the title compound,2-(((1s,4s)-4-((5-(2-fluoro-4-methylphenyl)-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid (25.0 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07-1.20 (m, 4H),1.21-1.39 (m, 4H), 1.60-1.75 (m, 1H), 1.90-1.99 (m, 1H), 2.23 (s, 3H),2.35 (s, 3H), 3.21 (d, J=6.95 Hz, 2H), 3.80 (bs, 2H), 4.92 (s, 2H),7.05-7.27 (m, 8H).

Example 1.18: Preparation of2-((1s,4s)-4-((3-(4-Chloro-2-fluorophenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 144)

A solution of 4-chloro-2-fluorophenylboronic acid (33.2 mg, 0.191 mmol),tert-butyl2-(((1s,4s)-4-((3-iodo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(100 mg, 0.191 mmol), tetrakis(triphenylphosphine)palladium (22.03 mg,0.019 mmol), and K₂CO₃ (2 M aqueous, 0.5 mL) in dioxane (3 mL) washeated to 150° C. under microwave irradiation for 2 h. The mixture wasfiltered and the filtrate was concentrated. The residue was treated withHCl (4 M in dioxane, 3 mL) at room temperature for 16 h. The mixture wasconcentrated and the residue was purified by HPLC to give the titlecompound (23.0 mg). LCMS m/z=471.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.32-1.53 (m, 8H), 1.70-1.80 (m, 1H), 2.02-2.12 (m, 1H), 2.29 (s,3H), 3.39 (d, J=6.95 Hz, 2H), 3.82 (s, 2H), 4.07 (d, J=7.45 Hz, 2H),7.03-7.10 (m, 2H), 7.18-7.41 (m, 6H).

Example 1.19: Preparation of2-(((1s,4s)-4-((5-(2-Hydroxyethylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 146) Step A: Preparation of2-(1,3-Dithietan-2-ylidene)-1,2-diphenylethanone

To a solution of 1,2-diphenylethanone (10.0 g, 51.0 mmol) in anhydrousTHF (100 mL) was added KOtBu (IM in THF, 51.0 mL, 51.0 mmol). Themixture was stirred for 30 min at room temperature, and carbon disulfide(7.76 g, 102 mmol) was added. After 10 min, dibromomethane (17.72 g, 102mmol) was added and the reaction was stirred for 4 h at roomtemperature. The reaction was quenched with water (10 mL) and dilutedwith EtOAc. The organic layer was separated, dried over MgSO₄, andconcentrated to give the title compound as a yellow solid (13.0 g).

LCMS m/z=285.0 [M+H]⁺.

Step B: Preparation of 3,4-Diphenyl-1H-pyrazole-5-thiol

To a suspension of 2-(1,3-dithietan-2-ylidene)-1,2-diphenylethanone(1.88 g, 6.61 mmol) in ethanol (50 mL) was added hydrazine hydrate(0.496 g, 9.92 mmol). The reaction was refluxed for 16 h, cooled to roomtemperature and concentrated. The residue was neutralized with HCl (1.0M) to pH 6-7 and extracted with EtOAc/H₂O. The organic extract was driedover MgSO₄ and concentrated to give the title compound (1.5 g). LCMSm/z=253.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 4.01-4.19 (m, 1H),6.92-7.58 (m, 10H).

Step C: Preparation of3,4-Diphenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazole

To a solution of 3,4-diphenyl-1H-pyrazole-5-thiol (1.2 g, 4.76 mmol) and2-(2-bromoethoxy)tetrahydro-2H-pyran (0.994 g, 4.76 mmol) in DMF (5 mL)was added K₂CO₃ (1.0 g, 7.23 mmol). The reaction was stirred at 60° C.for 2 h, cooled to room temperature, and quenched with H₂O (5 mL). Themixture was extracted with EtOAc, dried over MgSO₄, and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a colorless oil (1.7 g). LCMS m/z=381.2 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.32-1.50 (m, 4H), 1.50-1.73 (m, 2H), 2.99-3.13(m, 1H), 3.21-3.44 (m, 2H), 3.46-3.59 (m, 1H), 3.61-3.82 (m, 2H),4.44-4.59 (m, 1H), 7.16-7.40 (m, 10H), 13.32 (bs, 1H).

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-((3,4-Diphenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of3,4-diphenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazole(2.0 g, 5.26 mmol) in DMF (5 mL) was added sodium hydride (0.126 g, 5.26mmol) slowly at room temperature. The reaction was stirred at roomtemperature for 30 min, and tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (2.168 g, 5.26mmol) was added. The reaction was gently heated to 60° C. for 16 h.After cooled to room temperature, the reaction was quenched with H₂O (5mL). The mixture was extracted with EtOAc, dried over MgSO₄, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless oil (2.5 g).LCMS m/z=621.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.26-1.43 (m, 4H),1.44-1.54 (m, 4H), 1.47 (s, 9H), 1.54-1.62 (m, 2H), 1.76-1.92 (m, 4H),2.23-2.36 (m, 2H), 2.63 (t, J=6.69 Hz, 2H), 3.21-3.32 (m, 1H), 3.36 (d,J=6.95 Hz, 2H), 3.38-3.44 (m, 1H), 3.56-3.64 (m, 1H), 3.73 (t, J=11.18Hz, 1H), 3.91 (s, 2H), 3.93 (d, J=7.07 Hz, 2H), 4.33 (t, J=7.71 Hz, 1H),7.20-7.43 (m, 6H), 7.75-7.81 (m, 4H).

Step E: Preparation of2-(((1s,4s)-4-((5-(2-Hydroxyethylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

A mixture of tert-butyl2-(((1s,4s)-4-((3,4-diphenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(100 mg, 0.21 mmol) and HCl (4.0 M in dioxane, 4 mL) was stirred at roomtemperature for 16 h. The reaction mixture was concentrated and theresidue was purified by HPLC to give the title compound. LCMS m/z=481.4[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02-1.20 (m, 4H), 1.22-1.37 (m,4H), 1.55-1.64 (m, 1H), 1.88-1.99 (m, 1H), 3.03 (t, J=6.82 Hz, 2H), 3.20(d, J=6.82 Hz, 2H), 3.61 (t, J=6.82 Hz, 2H), 3.91 (s, 2H), 3.93 (d,J=7.20 Hz, 2H), 7.06-7.32 (m, I0H), 12.51 (br. s., 1H).

Example 1.20: Preparation of2-(((1s,4s)-4-((4-(3-Hydroxyphenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 153) Step A: Preparation of 5-Methyl-3-phenyl-1H-pyrazole

To a solution of acetophenone (10 g, 83 mmol) in anhydrous toluene (10mL) was added LiHMDS (1.0 M in THF, 83 mL, 83 mmol) via syringe at 0° C.under argon. After 5 min, acetyl chloride (6.53 g, 83 mmol) was addedvia syringe in one portion. The ice bath was removed and AcOH (5 mL,glacial), EtOH (50 mL), and hydrazine hydrate (12.50 g, 250 mmol) wereadded. The mixture was refluxed for 2 h, cooled to room temperature, andneutralized to pH 7 by adding 1.0 M NaOH solution. The mixture wasextracted with EtOAc, washed with brine, dried over MgSO₄, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale yellow oil (12.05g). LCMS m/z=159.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H),6.42 (s, 1H), 7.20-7.44 (m, 3H), 7.67-7.82 (m, 2H), 12.53 (bs, 1H).

Step B: Preparation of 4-Bromo-5-methyl-3-phenyl-1H-pyrazole

To a solution of 5-methyl-3-phenyl-1H-pyrazole (8.0 g, 50.6 mmol) indichloromethane (150 mL) was added bromine (8.08 g, 50.6 mmol) dropwiseat 0° C. The reaction was stirred at 0° C. for 30 min and then at roomtemperature for 2 h before quenching with aqueous Na₂SO₃ (10% w/w, 10mL). The organic solvent was removed and the aqueous phase was extractedwith EtOAc, washed with brine, dried over MgSO₄, and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a yellow oil (9.5 g). LCMS m/z=236.9 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3H), 7.30-7.57 (m, 5H), 13.12 (s, 1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 4-bromo-5-methyl-3-phenyl-1H-pyrazole (2.0 g, 8.44mmol) in DMF (5 mL) were added sodium hydride (0.202 g, 8.44 mmol) inportions at 0° C. The reaction was stirred at that temperature for 1 hand tert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(3.48 g, 8.44 mmol) was added. The reaction was gently heated to 42° C.for 16 h, cooled to room temperature, and quenched with H₂O (2 mL). Themixture was extracted with ethyl acetate, dried over MgSO₄ andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give the title compound as a colorlessliquid (3.05 g). LCMS m/z=477.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.26-1.50 (m, 8H), 1.43 (s, 9H), 1.66-1.78 (m, 1H), 1.97-2.09 (m, 1H),2.30 (s, 3H), 3.39 (d, J=6.82 Hz, 2H), 3.94 (s, 2H), 4.06 (d, J=7.58 Hz,2H), 7.30-7.50 (m, 3H), 7.74-7.85 (m, 2H).

Step D: Preparation of2-(((1s,4s)-4-((4-(3-Hydroxyphenyl)-5-methyl-3-phenyl-1I-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((4-iodo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(100 mg, 0.191 mmol) in dioxane (3 mL) was added 3-hydroxyphenylboronicacid (26.3 mg, 0.191 mmol), tetrakis(triphenylphosphine)palladium (22.03mg, 0.019 mmol), and K₂CO₃ (2 M aqueous, 0.2 mL, 0.4 mmol). The mixturewas heated to 150° C. under microwave irradiation for 4 h, filteredthrough a plug of silica gel, and concentrated. The residue was treatedwith HCl (4 M in dioxane, 3 mL) for 10 h. The mixture was concentratedand the residue was purified by HPLC to give the title compound (25.6mg). LCMS m/z=435.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.54(m, 8H), 1.70-1.81 (m, 1H), 2.03-2.13 (m, 1H), 2.19 (s, 3H), 3.42 (d,J=7.07 Hz, 2H), 3.99 (s, 2H), 4.03 (d, J=7.45 Hz, 2H), 6.52-6.73 (m,4H), 7.11-7.39 (m, 5H), 9.44 (bs, 1H).

Example 1.21: Preparation of2-(((1s,4s)-4-((5-(2-Methoxyethyl)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 178) Step A: Preparation of5-(2-Methoxyethyl)-3-phenyl-1H-pyrazole

To a solution of acetophenone (3.5 g, 29.1 mmol) in dry toluene (10 mL)was added LiHMDS (1.0 M in toluene) via syringe at 0° C. under argon.After 5 min, 3-methoxypropanoyl chloride (3.57 g, 29.1 mmol) was addedin one portion via syringe. The ice bath was removed and AcOH (2 mL),EtOH (100 mL), and hydrazine hydrate (4.37 g, 87 mmol) were added. Thereaction was refluxed for 2 h, cooled to room temperature, andconcentrated. The residue was extracted with EtOAc/H₂O, washed withbrine, dried over MgSO₄, and concentrated. The resulting residue waspurified by silica gel column chromatography to give the title compoundas a pale yellow oil (2.0 g).

LCMS m/z=203.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.85 (bs, 2H),3.27 (s, 3H), 3.59 (t, J=6.82 Hz, 2H), 6.49 (s, 1H), 7.21-7.46 (m, 3H),7.74 (m, 2H), 12.56 (s, 1H).

Step B: Preparation of 4-Bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazole

To a solution of 5-(2-methoxyethyl)-3-phenyl-1H-pyrazole (2.0 g, 9.89mmol) in DCM (100 mL) was added bromine (4.74 g, 29.7 mmol) dropwise at0° C. The reaction was stirred at 0° C. for 1 h and then at roomtemperature for 2 h before quenching with Na₂SO₃ (10% aqueous). Theorganic phase was removed and the aqueous layer was extracted with DCM(2×50 mL). The organic layers were combined, washed with brine, driedover MgSO₄, and concentrated to give the title compound (2.5 g). LCMSm/z=281.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.87 (t, J=6.82 Hz,2H), 3.27 (s, 3H), 3.62 (t, J=6.82 Hz, 2H), 5.75 (s, 1H), 7.35-7.51 (m,3H), 7.75-7.82 (m, 2H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazole (3.0 g,10.67 mmol) in DMF (5 mL) was added sodium hydride (0.256 g, 10.67mmol), followed by tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (4.40 g, 10.67mmol). The reaction was gently heated to 45° C. overnight. Afterquenching with water (5 mL), the mixture was extracted with EtOAc,washed with brine, dried over MgSO₄, and concentrated. The residue waspurified by silica gel column chromatography to give the title compound(4.5 g). LCMS m/z=523.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.69-1.80 (m, 4H), 1.81-1.89 (m, 4H), 1.91 (s, 9H), 2.19-2.30 (m, 2H),2.90 (s, 3H), 3.46 (t, J=6.63 Hz, 2H), 3.89 (d, J=6.95 Hz, 2H), 4.02 (t,J=6.32 Hz, 2H), 4.43 (s, 2H), 4.56 (d, J=7.45 Hz, 2H), 7.81-7.99 (m,3H), 8.24-8.32 (m, 2H).

Step D: Preparation of2-(((1s,4s)-4-((5-(2-Methoxyethyl)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(100 mg, 0.192 mmol) in dioxane (3 mL) was added phenylboronic acid(23.4 mg, 0.192 mmol), tetrakis(triphenylphosphine)palladium (22.03 mg,0.019 mmol), and K₂CO₃ (2 M aqueous, 0.5 mL). The reaction was heatedunder microwave irradiation at 150° C. for 4 h, filtered through a plugof silica gel and concentrated. The residue was treated with HCl (4M indioxane, 3 mL) for 10 h, and the mixture was purified by HPLC to givethe title compound (23.5 mg). LCMS m/z=463.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.33-1.56 (m, 8H), 1.71-1.84 (m, 1H), 2.05-2.20 (m, 1H),2.84 (t, J=6.82 Hz, 2H), 3.13 (s, 3H), 3.35 (t, J=6.82 Hz, 2H), 3.39 (d,J=7.07 Hz, 2H), 3.67 (s, 2H), 4.06 (d, J=7.33 Hz, 2H), 7.15-7.42 (m,10H).

Example 1.22: Preparation of2-(((1s,4s)-4-((5-(2-Methoxyethyl)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 179)

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(100 mg, 0.192 mmol) in dioxane (3 mL) was added 3-methoxyphenylboronicacid (23.4 mg, 0.192 mmol), tetrakis(triphenylphosphine)palladium (22.03mg, 0.019 mmol), and K₂CO₃ (2 M aqueous, 0.5 mL). The reaction washeated under microwave irradiation at 150° C. for 4 h, filtered througha plug of silica gel and concentrated. The residue was treated with HCl(4M in dioxane, 3 mL) for 10 h. The mixture was purified by HPLC to givethe title compound (23.5 mg). LCMS m/z=493.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.32-1.56 (m, 8H), 1.72-1.85 (m, 1H), 2.06-2.18 (m, 1H),2.85 (t, J=6.69 Hz, 2H), 3.16 (s, 3H), 3.36-3.38 (m, 2H), 3.40 (d,J=3.03 Hz, 2H), 3.66 (s, 2H), 3.70 (s, 3H), 4.05 (d, J=7.33 Hz, 2H),6.71-6.80 (m, 2H), 6.85-6.91 (m, 1H), 7.16-7.35 (m, 6H).

Example 1.23: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 215) Step A: Preparation of5-(2-(Methylthio)ethyl)-3-phenyl-1H-pyrazole

To a solution of acetophenone (5.0 g, 41.6 mmol) in dry toluene (10 mL)was added LiHMDS (1.0 M in toluene, 42 mL, 42 mmol) via syringe at 0° C.under argon. After 5 min, 3-(methylthio)propanoyl chloride (5.77 g, 41.6mmol) was added in one portion via syringe. The ice bath was removed andAcOH (5 mL), EtOH (100 mL), and hydrazine hydrate (6.25 g, 125 mmol)were added. The mixture was refluxed for 2 h, cooled to roomtemperature, and concentrated. The residue was partitioned between EtOAcand water, and the organic phase was washed with brine, dried overMgSO₄, and concentrated. The resulting residue was purified by silicagel column chromatography to give the title compound as a pale yellowoil (6.5 g). LCMS m/z=219.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.09(s, 3H), 2.77 (t, J=7.71 Hz, 2H), 2.84-2.95 (m, 2H), 6.53 (s, 1H),7.18-7.50 (m, 3H), 7.63-7.84 (m, 2H), 12.60 (bs, 1H).

Step B: Preparation of4-Bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazole

To a solution of 5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazole (4.0 g,18.32 mmol) in methanol (20 mL) was added N-bromosuccinimide (3.26 g,18.32 mmol) slowly at 0° C. The reaction was stirred at 0° C. for 2 h.The mixture was concentrated and purified by silica gel columnchromatography to give the title compound (3.4 g). LCMS m/z=297.0[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.11 (s, 3H), 2.79 (t, J=7.83Hz, 2H), 2.83-2.97 (m, 2H), 7.32-7.56 (m, 3H), 7.67-7.88 (m, 2H), 13.20(bs, 1H).

Step C: Preparation of tert-Butyl2-((1s,4s)-4-((4-Bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 4-bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazole(3.4 g, 11.44 mmol) in DMF (5 mL) was added sodium hydride (0.275 g,11.44 mmol) at room temperature, followed by tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (4.72 g, 11.44mmol). The reaction was heated to 45° C. overnight, cooled to roomtemperature, and quenched with water (5 mL). The mixture was extractedwith EtOAc, washed with brine, dried over MgSO₄, and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound (3.5 g). LCMS m/z=539.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.30-1.40 (m, 4H), 1.43 (s, 9H), 1.44-1.52 (m, 4H), 1.70-1.80 (m,1H), 2.03-2.11 (m, 1H), 2.14 (s, 3H), 2.72 (t, J=7.07 Hz, 2H), 3.00 (t,J=7.20 Hz, 2H), 3.40 (d, J=6.95 Hz, 2H), 3.94 (s, 2H), 4.09 (d, J=7.45Hz, 2H), 7.32-7.51 (m, 3H), 7.75-7.84 (m, 2H).

Step D: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(100 mg, 0.19 mmol) in dioxane (3 mL) were added2-fluoro-3-chlorophenylboronic acid (32.4 mg, 0.19 mmol),tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol), and K₂CO₃ (2M aqueous, 0.2 mL).

The reaction mixture was heated to 150° C. under microwave irradiationfor 4 h. The mixture was then filtered through a plug of silica gel andconcentrated, and the residue was treated with HCl (4 M in dioxane, 5mL) at room temperature for 10 h. The mixture was concentrated and theresidue was purified by HPLC to give the title compound (24.5 mg). LCMSm/z=531.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.55 (m, 8H),1.71-1.83 (m, 1H), 1.86 (s, 3H), 2.06-2.19 (m, 1H), 2.50 (t, J=7.83 Hz,2H), 2.85 (t, J=7.39 Hz, 2H), 3.40 (d, J=6.95 Hz, 2H), 3.71 (s, 2H),4.09 (d, J=7.33 Hz, 2H), 7.15-7.38 (m, 6H), 7.54-7.65 (m, 2H).

Example 1.24: Preparation of2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 31) Step A: Preparation of2-(3-Methoxyphenyl)-3,3-bis(methylthio)-1-phenylprop-2-en-1-one

To a solution of 2-(3-methoxyphenyl)-1-phenylethanone (5.0 g, 22.10mmol) in anhydrous THF (44.0 mL) was added a solution of potassiumtert-butoxide (1 M in THF, 46.0 mL, 46.0 mmol). The reaction mixture wasstirred for 15 min at room temperature, and then CS₂ (1.45 mL, 24.05mmol) was added. After several minutes, Mel (3.40 mL, 54.4 mmol) wasadded and the reaction was stirred for 5 h. Upon completion, thereaction mixture was diluted with saturated NaHCO₃ and extracted withEtOAc. The combined organic layers were washed with H₂O, brine, driedover MgSO₄ and concentrated to give the title compound as an orange oil.

Step B: Preparation of4-(3-Methoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazole

To a solution of2-(3-methoxyphenyl)-3,3-bis(methylthio)-1-phenylprop-2-en-1-one in EtOH(100 mL) was added hydrazine hydrate (5.36 mL, 110 mmol). The reactionmixture was refluxed overnight, additional hydrazine hydrate (1.00 mL,20.6 mmol) was added, and the mixture was refluxed until the reactionwas complete. The mixture was concentrated under reduced pressure,washed with H₂O and extracted with CH₂Cl₂. The combined organic layerswere washed with H₂O, brine, dried over MgSO₄ and concentrated to givethe title compound (6.67 g). LCMS m/z=397 [M+H]⁺.

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

In a reaction vial was placed4-(3-methoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazole (2.241 g, 7.56mmol) and NaH (357.4 mg, 8.94 mmol) in DMF (36.0 mL). The mixture wasstirred at room temperature for 15 min then a solution of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (3.0415 g, 7.37mmol) in DMF (10.0 mL) was added. The reaction was heated at 45° C. for15 h. Upon completion, the reaction mixture was quenched with H₂O andextracted with EtOAc. The combined organic layers were washed withbrine, dried over MgSO₄, and concentrated. The residue was purified bysilica gel column chromatography to give the title compound.

Step D: Preparation of2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To tert-butyl2-(((1s,4s)-4-((4-(3-methoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateobtained above was added 4 M HCl in dioxane. The reaction was stirred atroom temperature overnight. Upon completion, the reaction was basifiedwith 10% NaOH and organic impurities were extracted out with MTBE. Theaqueous layer was then acidified with 1 M HCl and extracted with MTBE.The combined organic layers were dried over MgSO₄ and concentrated. Theresidue obtained was dissolved in ACN and 1 N NaOH solution (2.45 mL,2.45 mmol) was added. The mixture was lyophilized to give a solid whichwas recrystallized from isopropyl alcohol to give the sodium salt of thetitle compound as an off-white solid (897.6 mg). LCMS m/z=481 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 1.17-1.80 (m, 10H), 2.14 (s, 3H), 3.34 (d,J=7.0 Hz, 2H), 3.50 (s, 2H), 3.71 (s, 3H), 4.27 (d, J=7.5 Hz, 2H),6.80-6.85 (m, 2H), 6.89-6.94 (m, 1H), 7.21-7.37 (m, 6H).

Example 1.25: Preparation of2-(((1s,4s)-4-((5-(2-Hydroxyethylthio)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 198) Step A: Preparation of4-(3-Methoxyphenyl)-3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazole

To a stirred solution of 2-(3-methoxyphenyl)-1-phenylethanone (1.25 g,5.52 mmol) in THF (11.05 mL) was added potassium tert-butoxide (11.49mL, 11.49 mmol). After 30 min, CS₂ (0.363 mL, 6.02 mmol) was added andthe mixture was stirred for 10 min before2-(2-bromoethoxy)tetrahydro-2H-pyran (2.086 mL, 13.81 mmol) was addedand the reaction was stirred overnight. The mixture was diluted withethanol (11.05 mL). Acetic acid (1.898 mL, 33.1 mmol) was added followedby hydrazine hydrate (2.71 mL, 55.2 mmol). The reaction was stirred at85° C. overnight and concentrated under reduced pressure. The residuewas extracted with EtOAc/H₂O (twice). The organic phases were combinedand washed with brine, dried over MgSO₄ and concentrated. The residuewas purified by silica gel column chromatography to give the titlecompound as a white solid (1.681 g). ¹H NMR (400 MHz, CDCl₃) δ ppm1.52-1.64 (m, 3H), 1.65-1.93 (m, 3H), 3.06 (t, J=5.94 Hz, 2H), 3.49-3.57(m, 1H), 3.65-3.71 (m, 1H), 3.72 (s, 3H), 3.88-3.95 (m, 1H), 3.97-4.05(m, 1H), 4.66-4.69 (m, 1H), 6.79-6.90 (m, 3H), 7.19-7.26 (m, 1H),7.26-7.33 (m, 3H), 7.37-7.45 (m, 2H), 10.91 (bs, 1H).

Step B: Preparation of tert-Butyl2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-5-phenyl-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-y)methyl)cyclohexyl)methoxy)acetate

To a stirred solution of4-(3-methoxyphenyl)-3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazole(0.123 g, 0.3 mmol) was added 60% NaH (0.012 g, 0.300 mmol). After 20min, tert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(0.124 g, 0.300 mmol) was added. The reaction was heated to 70° C. for18 h, cooled to room temperature, and diluted with water. The mixturewas extracted three times with EtOAc. The combined extracts were washedwith brine, dried over MgSO₄ and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound as amixture of regioisomers (46 mg). LCMS m/z=651.7 [M+H]⁺.

Step C: Preparation of2-(((1s,4s)-4-((5-(2-Hydroxyethylthio)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a stirred solution of tert-butyl2-(((1s,4s)-4-((4-(3-methoxyphenyl)-3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(46 mg, 0.071 mmol) and tert-butyl2-(((1s,4s)-4-((4-(3-methoxyphenyl)-5-phenyl-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(a mixture of regioisomers) in DCM (214 μL) was added water (21.42 μL),triethylsilane (113 μl, 0.707 mmol), and TFA (109 μL, 1.413 mmol). Thereaction was stirred overnight, further TFA (0.5 mL) was added and thereaction was stirred for an additional 1 h. The solvent was evaporated.The residue was taken up in 70% acetonitrile/water and purified by HPLC(50% acetonitrile/water; isocratic) to give the title compound as asolid. LCMS m/z=511.5 [M+H]⁺; 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.45(m, 4H), 1.45-1.54 (m, 4H), 1.69-1.80 (in, J=4.55 Hz, 1H), 2.18 (bs,1H), 2.51-2.56 (m, 2H), 2.60 (t, J=6.69 Hz, 2H), 2.60 (t, J=6.69 Hz,1H), 3.41 (d, J=7.07 Hz, 2H), 3.71 (s, 3H), 3.96-4.01 (m, 2H), 4.29 (d,J=7.58 Hz, 2H), 6.79-6.84 (m, 2H), 6.88-6.95 (m, 1H), 7.23-7.30 (m, 4H),7.30-7.37 (m, 2H).

Example 1.26: Preparation of2-(((1s,4s)-4-((5-(2-Hydroxyethylthio)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 200) Step A: Preparation of4-Phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-3-p-tolyl-1H-pyrazole

From 2-phenyl-1-p-tolylethanone, using a similar method to the onedescribed in Example 1.25, step A, the title compound was obtained as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.54-1.64 (m, 3H), 1.66-1.90(m, 3H), 2.33 (s, 3H), 3.05 (t, J=5.43 Hz, 2H), 3.47-3.56 (m, 1H),3.64-3.72 (m, 1H), 3.86-3.94 (m, 1H), 3.95-4.01 (m, 1H), 4.63-4.67 (m,1H), 7.10 (d, J=8.08 Hz, 2H), 7.25-7.30 (m, 5H), 7.30-7.39 (m, 2H).

Step B: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

From4-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-3-p-tolyl-1H-pyrazole,using a similar method to the one described in Example 1.25, step B, thetitle compound was obtained as a clear solid. LCMS m/z=635.6 [M+H]⁺.

Step C: Preparation of2-(((1s,4s)-4-((5-(2-Hydroxyethylthio)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1s,4s)-4-((4-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a method similar to the one described in Example 1.25, Step C, thetitle compound was obtained as a white solid.

LCMS m/z=495.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.45 (m,4H), 1.45-1.52 (m, 4H), 1.68-1.80 (m, 1H), 2.13-2.22 (m, 1H), 2.25 (s,3H), 2.56 (t, J=6.69 Hz, 2H), 3.23-3.29 (m, 2H), 3.41 (d, J=6.82 Hz,2H), 3.98-4.01 (m, 2H), 4.28 (d, J=7.58 Hz, 2H), 4.75 (bs, 1H), 7.06 (d,J=7.83 Hz, 2H), 7.20 (d, J=8.08 Hz, 2H), 7.23-7.28 (m, 2H), 7.30-7.43(m, 3H), 12.52 (bs, 1H).

Example 1.27: Preparation of2-(((1r,4r)-4-((3,4-Diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 8) and2-(((1r,4r)-4-((4,5-Diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 9) Step A: Preparation of 3,4-Diphenyl-1H-pyrazole

Phenyl(3-phenyloxiran-2-yl)methanone (5.0 g, 22.3 mmol) was suspended indry Et₂O (40 mL) under an argon balloon. Boron trifluoride diethyletherate (3.00 mL, 23.7 mmol) was added slowly via syringe. The reactionwas refluxed at 50° C. for an hour, then cooled and extracted with 60 mLeach of H₂O and Et₂O/EtOAc. The aqueous layer was extracted again withEtOAc (60 mL). The combined organic layer was dried and concentrated togive 3-oxo-2,3-diphenylpropanal.

3-Oxo-2,3-diphenylpropanal (5.00 g, 22.3 mmol) was dissolved in EtOH (40mL). Hydrazine monohydrate (2.0 mL, 38.7 mmol) was added slowly viasyringe. The reaction was stirred at room temperature for an hour. Thesolvent was evaporated and the residue was purified by silica gel columnchromatography to yield the title compound as a light purple solid (2.75g). LCMS m/z=221.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-ds) δ ppm 6.99-7.57 (m,10H), 7.66-8.09 (bs, 1H), 13.15 (bs, 1H).

Step B: Preparation of2-(((1r,4r)-4-((3,4-Diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid and2-(((1r,4r)-4-((4,5-Diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

3,4-Diphenyl-1H-pyrazole (16.02 mg, 0.073 mmol) was dissolved in DMF(0.4 mL). NaH (1.745 mg, 0.073 mmol) was added and the reaction wasstirred at room temperature for 15 min.tert-Butyl-2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(prepared in a similar manner to Example 1.1) (30.0 mg, 0.073 mmol) wasadded and the reaction was stirred at room temperature for an hour.After this time, the reaction was partitioned between with H₂O (2 mL)and EtOAc (2 mL). The aqueous layer was extracted with EtOAc (2 mL). Theorganic layers were combined, dried and concentrated. The resulting oilwas redissolved in HCl (4 M in dioxane) (400 μL, 1.600 mmol) and stirredovernight. The solvent was evaporated and the residue was purified bypreparative LC/MS (50% acetonitrile/water; isocratic) to yield Compound8 as a white solid (6.5 mg); LCMS m/z=405.5 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.86-1.12 (m, 4H), 1.44-1.58 (m, 1H), 1.61-1.71 (m, 2H),1.73-1.80 (m, 2H), 1.80-1.91 (m, 1H), 3.26 (d, J=6.32 Hz, 2H), 3.95 (s,2H), 4.00 (d, J=7.07 Hz, 2H), 7.20-7.27 (m, 3H), 7.27-7.36 (m, 5H),7.36-7.44 (m, 2H), 7.92 (s, 1H); and Compound 9 as a white solid (1.0mg); LCMS m/z=405.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.68-0.88(m, 4H), 1.33-1.50 (m, J=9.98 Hz, 3H), 1.57-1.78 (m, 3H), 3.20 (d,J=6.32 Hz, 2H), 3.78 (d, J=7.20 Hz, 2H), 3.92 (s, 2H), 7.07-7.16 (m,3H), 7.16-7.22 (m, 2H), 7.30-7.36 (m, 2H), 7.47-7.56 (m, 3H), 7.83 (s,1H).

Example 1.28: Preparation of2-(((1s,4s)-4-((1-Phenyl-4,5-dihydro-3H-benzo[e]indazol-3-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 150) Step A: Preparation of1-Phenyl-4,5-dihydro-3H-benzo[e]indazole

3,4-Dihydronaphthalen-2(1H)-one (2.080 g, 14.23 mmol) was dissolved intoluene (15 mL) and the solution was cooled on an ice bath. LiHMDS(7.470 mL, 7.470 mmol) was added with vigorous stirring. One minutelater benzoyl chloride (0.8258 mL, 7.114 mmol) was added. The reactionwas removed from the ice bath and stirred for another minute. AcOH (4mL) was added with stirring, followed by EtOH (10 mL), THF (5 mL), andhydrazine monohydrate (5 mL, 96.8 mmol). After 10 min, the solution waspoured into a seperatory funnel loaded with 1M NaOH (30 mL) andextracted with additional H₂O (70 mL) and EtOAc (100 mL). The aqueouslayer was extracted again with EtOAc (100 mL). The combined organiclayer was dried and concentrated. The residue was purified by silica gelcolumn chromatography to yield the title compound as a light-purplecolored solid. LCMS m/z=247.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.72-2.86 (m, 2H), 2.90-3.00 (m, 2H), 6.99-7.09 (m, 2H), 7.11-7.21 (m,1H), 7.23-7.29 (m, 1H), 7.37-7.61 (m, 5H), 12.75 (s, 0.7H), 12.97 (s,0.3H).

Step B: Preparation of2-(((1s,4s)-4-((1-Phenyl-4,5-dihydro-3H-benzo[e]indazol-3-yl)methyl)cyclohexyl)methoxy)aceticAcid

I-Phenyl-4,5-dihydro-3H-benzo[e]indazole (100 mg, 0.406 mmol) wasdissolved in DMF (0.4 mL). Sodium hydride (9.74 mg, 0.406 mmol) wasadded. The reaction was stirred at room temperature for 10 min and thentert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl) methoxy)acetate(167 mg, 0.406 mmol), pre-dissolved in DMF (0.2 mL) was added. Thereaction was stirred for 1 h at 50° C. After this time, more NaH (10 mg)was added. The reaction was again stirred for 1 h at 50° C. The mixturewas extracted with 15 mL each of H₂O and EtOAc. The aqueous layer wasextracted again with EtOAc (15 mL). The combined organic layer was driedand concentrated. The residue was redissolved in HCl (4 M in dioxane)(507 μL, 2.030 mmol) and stirred overnight at room temperature. Thesolvent was evaporated and the residue was purified by preparative LC/MSto give the title compound as a light-tan solid (35 mg). LCMS m/z=431.4[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28-1.54 (m, 8H), 1.69-1.80 (m,1H), 2.00-2.10 (m, 1H), 2.85 (d, J=7.83 Hz, 2H), 2.97 (t, J=7.33 Hz,2H), 3.41 (d, J=6.95 Hz, 2H), 3.99 (s, 2H), 4.04 (d, J=7.58 Hz, 2H),6.98-7.08 (m, 2H), 7.10-7.18 (m, 1H), 7.22-7.30 (m, 1H), 7.35-7.50 (m,3H), 7.54-7.60 (m, 2H).

Example 1.29: Preparation of2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 143) Step A: Preparation of (1s,4s)-Ethyl4-(Hydroxymethyl)cyclohexanecarboxylate

To a solution of (1s,4s)-4-(hydroxymethyl)cyclohexanecarboxylic acid (10g, 63.2 mmol) in ethanol (100 mL), was added sulfuric acid (0.31 g, 3.16mmol) at room temperature. After heating for 10 h at 85° C., thereaction was cooled to room temperature and concentrated under reducedpressure. The residue was extracted with ethyl acetate, dried overMgSO₄, and then concentrated under reduced pressure to give the titlecompound (4.98 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (t, J=7.1 Hz,3H), 1.40-1.54 (m, 7H), 2.55 (m, 1H), 1.82 (m, 2H), 3.21 (d, J=6.4 Hz,2H), 4.01 (q, J=7.1 Hz, 2H).

Step B: Preparation of ((1s,4s)-4-(Benzyloxymethyl)cyclohexyl)methanol

To a solution of (1s,4s)-ethyl 4-(hydroxymethyl)cyclohexanecarboxylate(5 g, 26.8 mmol) in DMF (50 mL) was added (bromomethyl)benzene (4.59 g,26.8 mmol) followed by NaH (0.644 g, 26.8 mmol) at 0° C. After stirringfor 4 h at room temperature, the mixture was poured into water andextracted with ethyl acetate. The extract was dried over MgSO₄ andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give (1s,4s)-ethyl4-(benzyloxymethyl)cyclohexanecarboxylate (3.2 g, 13.66 mmol). The abovematerial was dissolved in THF (50 mL) and lithium aluminum hydride (1.02g, 26.8 mmol) was added at 0° C. After stirring for 1 h at roomtemperature, the reaction was quenched with H_(z)O (5 mL) at 0° C. Afterstirring at room temperature for 1 h, the resulting precipitate wasfiltered off. The filtrate was dried over MgSO₄ and concentrated underreduced pressure to give the title compound (3.2 g). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.84-0.99 (m, 7H), 1.35 (m, 1H), 1.46 (m, 1H), 1.52 (m,1H), 3.23 (d, J=7.0 Hz, 2H), 3.25 (d, J=5.7 Hz, 2H), 4.45 (s, 2H),7.21-7.40 (m, 5H).

Step C: Preparation of(1s,4s)-4-(Benzyloxymethyl)cyclohexanecarbaldehyde

To a solution of DMSO (1.32 mL, 18.78 mmol) in CH₂Cl₂ (50 mL) was addedoxalyl dichloride (1.19 g, 9.39 mmol) dropwise at −50° C. After stirringfor 10 min, ((1s,4s)-4-(benzyloxymethyl)cyclohexyl)methanol (2.0 g, 8.53mmol) and triethylamine (4.32 g, 42.7 mmol) were added at the sametemperature. After stirring for 1 h at room temperature, the reactionwas extracted with CH₂C₂ and dried over MgSO₄. The organic layer wasconcentrated under reduced pressure to give the title compound (1.9 g).¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.91-1.21 (m, 6H), 1.45 (m, 1H),1.75-1.95 (m, 2H), 2.25 (m, 1H), 3.25 (d, J=7.1 Hz, 2H), 4.42 (s, 2H),7.25-7.42 (m, 5H), 9.52 (s, 1H).

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-(Benzyloxymethyl)cyclohexyl)methyl)hydrazinecarboxylate

To a solution of (1s,4s)-4-(benzyloxymethyl)cyclohexanecarbaldehyde (1.2g, 5.17 mmol) in MeOH (50 mL) was added tert-butyl hydrazinecarboxylate(0.68 g, 5.17 mmol) at room temperature. After stirring for 1 h, thereaction was concentrated under reduced pressure. The residue wasdissolved in MeOH (25 mL) and acetic acid (25 mL). NaCNBH₃ (0.33 g, 5.17mmol) was added at 0° C. After stirring for 30 min, the reaction wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate and washed with 0.1 M NaOH. The extract was dried over MgSO₄ andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give the title compound (0.85 g). LCMSm/z=349.4 [M+H]⁺.

Step E: Preparation of1-(((1s,4s)-4-(Benzyloxymethyl)cyclohexyl)methyl)-2-(2-fluoro-4-methylbenzylidene)hydrazine

To a solution of tert-butyl1-(((1s,4s)-4-(benzyloxymethyl)cyclohexyl)methyl)hydrazinecarboxylate(1.0 g, 2.87 mmol) in CH₂Cl₂ (5 mL), was added TFA (5.0 mL) at roomtemperature. After stirring for 3 h at the same temperature, thereaction was concentrated under reduced pressure. The residue wasdissolved in THF (10 mL) and 2-fluoro-4-methylbenzaldehyde (0.40 g, 2.87mmol) was added. After stirring for 30 min, the reaction was washed withsaturated NaHCO₃. The organics were dried over MgSO₄ and concentratedunder reduced pressure to give the title compound (0.96 g). LCMSm/z=369.3 [M+H]⁺.

Step F: Preparation of1-(((1s,4s)-4-(Benzyloxymethyl)cyclohexyl)methyl)-3-(2-fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazole

To a solution of1-(((1s,4s)-4-(benzyloxymethyl)cyclohexyl)methyl)-2-(2-fluoro-4-methylbenzylidene)hydrazine(0.5 g, 1.357 mmol) and (2-nitroprop-1-enyl)benzene (0.22 g, 1.36 mmol)in THF (5 mL) at −78° C., was added potassium butan-1-olate (0.152 g,1.357 mmol) dropwise. After 10 min, TFA (0.21 mL, 2.71 mmol) was addedat the same temperature and maintained for 2 h. After warming to roomtemperature, the reaction was extracted with ethyl acetate, dried overMgSO₄, and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to give the title compound(0.49 g). LCMS m/z=483.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.34-1.52 (m, 8H), 1.85 (m, 1H), 2.15 (m, 1H), 2.25 (s, 3H), 2.31 (s,3H), 3.34 (d, J=7.0 Hz, 2H), 4.25 (d, J=7.4 Hz, 2H), 4.51 (s, 2H),6.92-7.38 (m, 4H), 7.39-7.45 (m, 9H).

Step G: Preparation of((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methanol

To a solution of1-(((1s,4s)-4-(benzyloxymethyl)cyclohexyl)methyl)-3-(2-fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazole(100 mg, 0.21 mmol) in MeOH (5 mL), was added ammonium formate (261 mg,4.14 mmol) followed by 10% Pd/C (5 mg). The reaction was heated to 80°C. for 10 h. After filtration of insoluble material, the reaction wasconcentrated under reduced pressure to give the title compound as acolorless oil (78 mg). LCMS m/z=393.3 [M+H]⁺.

Step H: Preparation of tert-Butyl2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of((1s,4s)-4-((3-(2-fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methanol(20 mg, 0.051 mmol) and (Rh(OAc)₂)₂(2.25 mg, 5.10 μmol) in CH₂Cl₂ (2mL), was added a solution of tert-butyl 2-diazoacetate (7.24 mg, 0.051mmol) in CH₂Cl₂ (0.5 mL) dropwise for 10 min at −10° C. The reaction wasstirred for 1 h at the same temperature. The solid material was filteredoff and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to give thetitle compound (20 mg).

LCMS m/z=507.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.45 (m,17H), 1.75 (m, 1H), 2.11 (m, 1H), 2.28 (s, 3H), 2.30 (s, 3H), 3.52 (d,J=7.0 Hz, 2H), 3.95 (s, 2H), 4.05 (d, J=7.3 Hz, 2H), 6.90 (d, J=11.5 Hz,1H), 6.95 (d, J=7.7 Hz, 1H), 7.05-7.33 (m, 6H).

Step I: Preparation of2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

tert-Butyl2-(((1s,4s)-4-((3-(2-fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(250 mg, 0.49 mmol) was treated with HCl (4.0 M in dioxane, 10 mL) atroom temperature. After stirring for 12 h, the reaction was concentratedin vacuo and purified by HPLC. The free acid was dissolved inacetonitrile (5 mL) and H₂O (2 mL), added into a solution of sodiumhydroxide (19.74 mg, 0.49 mmol) in H₂O (10 mL), and dried under reducedpressure to give the sodium salt of the title compound (149 mg). LCMSm/z=451.2 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.52 (m, 8H),1.71-1.81 (m, 1H), 2.02-2.13 (m, 1H), 2.28 (s, 3H), 2.30 (s, 3H), 3.37(d, J=6.7 Hz, 2H), 3.61 (s, 2H), 4.05 (d, J=7.3 Hz, 2H), 6.91 (d, J=11.2Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 7.05 (s, 1H), 7.07 (s, 1H), 7.16-7.32(m, 4H).

Example 1.30: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-(2-hydroxyethylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 199) Step A: Preparation of4-(3-Chlorophenyl)-3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazole

From 2-(3-chlorophenyl)-1-phenethanone, using a similar method to theone described in Example 1.25, Step A, the title compound was obtainedas a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.51-1.65 (m, 3H),1.66-1.92 (m, 3H), 3.07 (t, J=5.81 Hz, 2H), 3.49-3.59 (m, 1H), 3.66-3.75(m, 1H), 3.87-3.96 (m, 1H), 3.97-4.04 (m, 1H), 4.68 (dd, J=4.29, 3.03Hz, 1H), 7.09-7.15 (m, 1H), 7.23-7.27 (m, 2H), 7.28-7.33 (m, 4H),7.34-7.42 (m, 2H), 10.95 (bs, 1H).

Step B: Preparation of tert-Butyl2-(((1s,4s)-4-((4-(3-Chlorophenyl)-3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-phenyl-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

From4-(3-chlorophenyl)-3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazole,using a similar method to the one described in Example 1.25, Step B, thetitle compound was obtained as a clear oil (a mixture of regioisomers).LCMS m/z=655.4 [M+H]⁺.

Step C: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-(2-hydroxyethylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1s,4s)-4-((4-(3-chlorophenyl)-3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-(3-chlorophenyl)-5-phenyl-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers, using a similar method to the onedescribed in Example 1.25, Step C, the title compound was obtained as aclear solid. LCMS m/z=515.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.32-1.54 (m, 8H), 1.71-1.79 (m, 1H), 2.11-2.23 (m, 1H), 2.51-2.55 (m,2H), 2.61 (t, J=6.57 Hz, 2H), 3.30 (t, J=6.57 Hz, 1H), 3.41 (d, J=6.82Hz, 2H), 3.98 (s, 2H), 4.30 (d, J=7.58 Hz, 2H), 7.18-7.23 (m, 1H),7.25-7.34 (m, 6H), 7.38-7.44 (m, 2H).

Example 1.31: Preparation of2-((1s,4s)-4-((5-(2-Hydroxyethylthio)-3-phenyl-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 210) Step A: Preparation of3-Phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-4-m-tolyl-1H-pyrazole

From 1-phenyl-2-m-tolylethanone, using a similar method to the onedescribed in Example 1.25, Step A, the title compound was obtained as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.51 (m, 4H),1.52-1.73 (m, 2H), 2.26 (s, 3H), 3.10 (t, J=6.82 Hz, 2H), 3.32-3.45 (m,1H), 3.53-3.67 (m, 1H), 3.68-3.76 (m, 1H), 3.76-3.84 (m, 1H), 4.55 (t,J=3.16 Hz, 1H), 6.97 (d, J=7.33 Hz, 1H), 7.04 (s, 1H), 7.08-7.14 (m,1H), 7.20-7.27 (m, 2H), 7.29-7.37 (m, 4H), 13.30 (s, 1H).

Step B: Preparation of tert-Butyl2-(((1s,4s)-4-((3-Phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((5-Phenyl-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

From3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-4-m-tolyl-1H-pyrazole,using a similar method to the one described in Example 1.25, Step B, thetitle compound was obtained as a clear oil (a mixture of regioisomers).LCMS m/z=635.7 [M+H]⁺.

Step C: Preparation of2-(((1s,4s)-4-((5-(2-Hydroxyethylthio)-3-phenyl-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1s,4s)-4-((3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-phenyl-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers, using a similar method to the onedescribed in Example 1.25, Step C, the title compound was obtained as ayellow oily solid. LCMS m/z=495.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.33-1.44 (m, 4H), 1.44-1.53 (m, 4H), 1.68-1.80 (m, 1H), 2.13-2.23(m, 1H), 2.30 (s, 3H), 2.58 (t, J=6.69 Hz, 2H), 3.17 (d, J=5.05 Hz, 1H),3.26-3.35 (m, 2H), 3.41 (d, J=7.07 Hz, 2H), 3.99 (s, 2H), 4.29 (d,J=7.58 Hz, 2H), 7.02 (d, J=7.58 Hz, 1H), 7.10 (s, 1H), 7.16 (d, J=7.83Hz, 1H), 7.22-7.29 (m, 4H), 7.30-7.35 (m, 2H).

Example 1.32: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-5-(2-hydroxyethylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 212) Step A: Preparation of4-(3-Fluoorophenyl)-3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazole

From 2-(3-fluorophenyl)-1-phenethanone, using a similar method to theone described in Example 1.25, Step A, the title compound was obtainedas a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.51 (m, 4H),1.50-1.75 (m, 2H), 3.12 (t, J=6.69 Hz, 2H), 3.33-3.43 (m, 1H), 3.52-3.66(m, 1H), 3.67-3.76 (m, 1H), 3.76-3.84 (m, 1H), 4.55 (t, J=3.28 Hz, 1H),6.96-7.05 (m, 2H), 7.08-7.15 (m, 1H), 7.23-7.44 (m, 6H), 13.41 (s, 1H).

Step B: Preparation of tert-Butyl2-(((1s,4s)-4-((4-(3-Fluoorophenyl)-3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-(3-Fluoorophenyl)-5-phenyl-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

From4-(3-fluorophenyl)-3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazole,using a similar method to the one described in Example 1.25, Step B, thetitle compound was obtained as a clear oil (a mixture of regioisomers).LCMS m/z=639.5 [M+H]⁺.

Step C: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-5-(2-hydroxyethylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1s,4s)-4-((4-(3-fluoorophenyl)-3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-(3-fluoorophenyl)-5-phenyl-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate as amixture of regioisomers, using a similar method to the one described inExample 1.25, Step C, the title compound was obtained as a clear oilysolid. LCMS m/z=499.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.45(m, 4H), 1.45-1.53 (m, 4H), 1.69-1.81 (m, 1H), 2.11-2.22 (m, 1H),2.43-2.56 (m, 2H), 2.60 (t, J=6.69 Hz, 1H), 3.21-3.33 (m, 2H), 3.41 (d,J=7.07 Hz, 2H), 3.99-4.00 (m, 2H), 4.30 (d, J=7.58 Hz, 2H), 7.05-7.12(m, 2H), 7.13-7.22 (m, 1H), 7.23-7.34 (m, 5H), 7.38-7.46 (m, 1H), 12.52(s, 1H).

Example 1.33: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-(2-hydroxyethylsulfinyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 217)

To a solution of2-(((1s,4s)-4-((4-(3-chlorophenyl)-5-(2-hydroxyethylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid (18.3 mg, 0.036 mmol) in DCM (178 L) was added mCPBA (5.82 mg,0.034 mmol). The reaction was stirred for 20 min and concentrated underreduced pressure. The residue was taken up in ACN/H₂O and purified viapreparative HPLC to give the title compound (9.7 mg) as a white solid.LCMS m/z=531.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.55 (m,J=4.29 Hz, 8H), 1.72-1.80 (m, 1H), 2.26 (bs, 1H), 2.98-3.10 (m, 1H),3.25-3.28 (m, 2H), 3.40 (d, J=7.20 Hz, 1H), 3.57-3.66 (m, 1H), 3.68-3.77(m, 1H), 3.99 (s, 2H), 4.28-4.50 (m, 2H), 5.08 (bs, 1H), 7.21-7.27 (m,1H), 7.27-7.33 (m, 5H), 7.38-7.46 (m, 3H), 12.51 (s, 1H).

Example 1.34: Preparation of2-(((1s,4s)-4-((5-(2-Aminoethylthio)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 250) Step A: Preparation of tert-Butyl2-(4-Phenyl-3-p-tolyl-1H-pyrazol-5-ylthio)ethylcarbamate

From 2-phenyl-1-p-tolylethanone and tert-butyl 2-bromoethylcarbamate,using a similar method to the one described in Example 1.25, Step A, thetitle compound was obtained as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.36 (s, 9H), 2.28 (s, 3H), 2.71-2.78 (m, 1H), 2.94 (t,J=7.07 Hz, 2H), 3.13-3.21 (m, 2H), 6.88 (t, J=5.68 Hz, 1H), 7.13-7.23(m, 6H), 7.32-7.37 (m, 2H), 13.26 (s, 1H).

Step B: Preparation of tert-Butyl2-(((1s,4s)-4-((5-(2-(tert-Butoxycarbonylamino)ethylthio)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((3-(2-(tert-Butoxycarbonylamino)ethylthio)-4-phenyl-5-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

From tert-butyl2-(4-phenyl-3-p-tolyl-1H-pyrazol-5-ylthio)ethylcarbamate, using asimilar method to the one described in Example 1.25, Step B, the titlecompound was obtained as a clear oil (a mixture of regioisomers). LCMSm/z=650.7 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (s, 9H),1.36-1.46 (m, 3H), 1.43 (s, 9H), 1.45-1.52 (m, 3H), 1.68-1.80 (m, 1H),2.12-2.21 (m, 1H), 2.25 (s, 3H), 2.51-2.55 (m, 2H), 2.83 (q, J=6.61 Hz,2H), 3.14-3.19 (m, 2H), 3.40 (d, J=6.82 Hz, 2H), 3.95 (s, 2H), 4.26 (d,J=7.58 Hz, 2H), 6.64-6.75 (m, 1H), 7.05 (d, J=7.96 Hz, 2H), 7.20 (d,J=8.08 Hz, 2H), 7.23-7.27 (m, 2H), 7.30-7.42 (m, 3H).

Step C: Preparation of2-(((1s,4s)-4-((5-(2-Aminoethylthio)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetic Acid

From tert-butyl2-(((1s,4s)-4-((5-(2-(tert-butoxycarbonylamino)ethylthio)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-(2-(tert-butoxycarbonylamino)ethylthio)-4-phenyl-5-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers, using a similar method to the onedescribed in Example 1.25, Step C, the title compound was obtained as awhite solid.

LCMS m/z=494.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.46 (m,J=23.31, 5.62 Hz, 4H), 1.46-1.54 (m, 4H), 1.70-1.85 (m, 1H), 2.14-2.23(m, 1H), 2.26 (s, 3H), 2.57-2.74 (m, 4H), 3.42 (d, J=7.07 Hz, 2H), 4.00(s, 2H), 4.28 (d, J=7.45 Hz, 2H), 7.07 (d, J=7.96 Hz, 2H), 7.20 (d,J=8.08 Hz, 2H), 7.24-7.29 (m, 2H), 7.31-7.45 (m, 3H), 7.64 (bs, 2H),12.54 (s, 1H).

Example 1.35: Preparation of2-(((1s,4s)-4-((3-(4-Fluorophenyl)-5-(2-hydroxyethylthio)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 255) Step A: Preparation of3-(4-Fluorophenyl)-4-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazole

From 1-(4-fluorophenyl)-2-phenethanone, using a similar method to theone described in Example 1.25, Step A, the title compound was obtainedas a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.51 (m, 3H),1.52-1.75 (m, 3H), 3.10 (t, J=6.63 Hz, 2H), 3.33-3.44 (m, 1H), 3.53-3.66(m, 1H), 3.68-3.83 (m, 2H), 4.52-4.57 (m, 1H), 7.11 (t, J=8.27 Hz, 1H),7.21 (t, J=8.97 Hz, 3H), 7.24-7.43 (m, 5H), 13.34 (s, 1H).

Step B: Preparation of tert-butyl2-(((1s,4s)-4-((3-(4-Fluorophenyl)-4-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((5-(4-Fluorophenyl)-4-phenyl-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

From4-(3-fluorophenyl)-3-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazole,using a similar method to the one described in Example 1.25, Step B, thetitle compound was obtained as a clear oil (a mixture of regioisomers).LCMS m/z=639.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.42 (m,4H), 1.43 (s, 9H), 1.45-1.54 (m, 7H), 1.56-1.79 (m, 3H), 2.14-2.24 (m,1H), 2.65-2.72 (m, 2H), 3.20-3.28 (m, 2H), 3.31-3.37 (m, 1H), 3.39 (d,J=6.82 Hz, 2H), 3.47-3.56 (m, 1H), 3.58-3.66 (m, 1H), 3.95 (s, 2H), 4.30(dd, J=7.39, 3.09 Hz, 2H), 4.34-4.36 (m, 1H), 7.06-7.13 (m, 2H),7.24-7.28 (m, 2H), 7.29-7.44 (m, 5H).

Step C: Preparation of2-(((1s,4s)-4-((3-(4-Fluorophenyl)-5-(2-hydroxyethylthio)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1s,4s)-4-((3-(4-fluorophenyl)-4-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-(4-fluorophenyl)-4-phenyl-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.25, Step C, thetitle compounds were obtained as clear oily solids. LCMS m/z=499.7[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29-1.45 (m, 4H), 1.45-1.53 (m,4H), 1.69-1.80 (m, 1H), 2.14-2.22 (m, 1H), 2.57 (t, J=6.69 Hz, 2H),3.25-3.29 (m, 2H), 3.28-3.32 (m, 1H), 3.40 (d, J=6.95 Hz, 2H), 3.97 (s,2H), 4.29 (d, J=7.45 Hz, 2H), 7.06-7.14 (m, 2H), 7.23-7.28 (m, 2H),7.30-7.43 (m, 5H).

Example 1.36: Preparation of2-(((1s,4s)-4-((5-(4-Fluorophenyl)-3-(2-hydroxyethylthio)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 256)

From tert-butyl2-(((1s,4s)-4-((3-(4-fluorophenyl)-4-phenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-(4-fluorophenyl)-4-phenyl-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.25, Step C, thetitle compound was obtained as clear oil solid. LCMS m/z=499.7 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81-0.99 (m, 2H), 1.01-1.14 (m, 2H),1.46-1.59 (m, 1H), 1.65 (dd, J=13.20, 2.08 Hz, 2H), 1.76 (dd, J=12.44,2.08 Hz, 2H), 1.86-1.97 (m, 1H), 2.56 (t, J=6.63 Hz, 2H), 3.27 (dd,J=13.52, 6.69 Hz, 4H), 3.91 (s, 2H), 4.20 (d, J=7.20 Hz, 2H), 4.76 (bs,1H), 7.07-7.14 (m, 2H), 7.25-7.28 (m, 2H), 7.31-7.43 (m, 5H).

Example 1.37: Preparation of2-(((1s,4s)-4-((5-(2-Hydroxyethyl)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 251) Step A: Preparation of2-(3-Phenyl-1H-pyrazol-5-yl)ethanol

5-(2-(Benzyloxy)ethyl-3-phenyl-1H-pyrazole (2.1 g, 7.54 mmol) wasdissolved in acetic acid (10 mL) and THF (10 mL). Palladium on carbon(0.080 g, 0.754 mmol) was added and the reaction was stirred for 4 daysunder hydrogen atmosphere on the Parr shaker at 55 psi. After this time,the reaction was filtered through celite and washed with EtOAc. Thesolvents were evaporated. The reaction progress was checked by TLC andshown to be 50-60% complete. The reaction was set up on the Parr shakeragain. After three more days on the Parr shaker, the reaction wasstopped. The reaction was filtered through celite and the solventsremoved. The reaction was extracted (70 mL each of H₂O and EtOAc). Theaqueous layer was extracted again with EtOAc (70 mL). The combinedorganic layer was dried and concentrated, and the residue was purifiedby column chromatography to give the title compound (665 mg) as a whitesolid.

LCMS m/z=189.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.68-2.82 (m,2H), 3.60-3.71 (m, 2H), 4.73-4.81 (m, 1H), 6.48 (s, 1H), 7.20-7.49 (m,3H), 7.55-7.96 (m, 2H), 12.53 (s, 1H).

Step B: Preparation of 2-(4-Bromo-3-phenyl-1H-pyrazol-5-yl)ethanol

2-(3-Phenyl-1H-pyrazol-5-yl)ethanol (664 mg, 3.53 mmol) was dissolved indry DCM (40 mL) and THF (10 mL). The reaction was cooled in an ice bathand Br₂ (363 μL, 7.06 mmol), pre-dissolved in DCM (3 mL), was addedslowly dropwise via addition funnel. The reaction was stirred for 2 h inan ice bath, then the reaction was quenched by the addition of Na₂SO₃(20 mL of 10% solution; the reaction went from reddish-brown to clearand some bubbling was observed). The reaction was extracted (100 mL eachof H₂O and DCM). The aqueous layer was extracted again with DCM (100mL). The combined organic layer was back extracted again with H₂O (200mL). The organic layer was dried and concentrated to yield the titlecompound (880 mg) as a light yellow solid. LCMS m/z=267.1 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.78 (t, J=7.14 Hz, 2H), 3.66 (t, J=7.14 Hz,2H), 7.35-7.42 (m, 1H), 7.43-7.51 (m, 2H), 7.72-7.84 (m, 2H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-(2-hydroxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

2-(4-Bromo-3-phenyl-1H-pyrazol-5-yl)ethanol (880 mg, 3.29 mmol),tert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(1359 mg, 3.29 mmol), and cesium carbonate (2147 mg, 6.59 mmol) wereadded to DMF (15 mL). The reaction was heated to 80° C. and stirred atthis temperature for 1 h. The reaction was cooled and extracted (50 mLeach of H₂O and EtOAc). The aqueous layer was extracted again with EtOAc(50 mL). The combined organic layer was back extracted with H₂O (100mL). The organic layer was dried, concentrated, and the residue waspurified by chromatography to yield the title compound (640 mg) as alight yellow oil. LCMS m/z=507.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.28-1.53 (m, 17H), 1.69-1.81 (m, J=5.31 Hz, 1H), 2.02-2.14 (m, 1H),2.87 (t, J=6.76 Hz, 2H), 3.39 (d, J=6.95 Hz, 2H), 3.56-3.66 (m, 2H),3.94 (s, 2H), 4.10 (d, J=7.45 Hz, 2H), 4.92 (t, J=5.43 Hz, 1H),7.33-7.40 (m, 1H), 7.40-7.49 (m, 2H), 7.75-7.85 (m, 2H).

Step D: Preparation of2-(((1s,4s)-4-((5-(2-Hydroxyethyl)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

tert-Butyl2-(((1s,4s)-4-((4-bromo-5-(2-hydroxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(30 mg, 0.059 mmol), phenyl boronic acid (1.1 eq),tetrakistriphenylphosphinepalladium (3.42 mg, 2.96 μmol), and K₂CO₃(16.34 mg, 0.118 mmol) were added to a vial with dioxane (300 μL). Thereaction was heated in a microwave at 150° C. for 1 h. After this time,the reaction was filtered through a plug of MgSO₄. The solvent wasremoved and the resulting oil (t-butyl ester intermediate) wasre-dissolved in HCl (500 μL, 2.000 mmol). The reaction was stirredovernight at room temperature. The next day, the solvent was removed andthe product was purified by preparative LC/MS to give the title compound(4.2 mg) as a white solid. LCMS m/z=449.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.33-1.59 (m, 8H), 1.73-1.82 (m, 1H), 2.09-2.21 (m, 1H),2.75 (t, J=7.14 Hz, 2H), 3.40-3.46 (m, 4H), 3.98-4.00 (m, 2H), 4.06-4.09(m, 2H), 7.15-7.25 (m, 5H), 7.26-7.34 (m, 3H), 7.34-7.42 (m, 2H).

Example 1.38: Preparation of2-(((1s,4s)-4-((5-(2-Hydroxyethyl)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 252)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-hydroxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand 3-methoxyphenylboronic acid, using a similar method to the onedescribed in Example 1.37, the title compound was obtained as a whitesolid.

LCMS m/z=479.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.59 (m,8H), 1.71-1.86 (m, 1H), 2.06-2.22 (m, 1H), 2.76 (t, J=6.19 Hz, 2H),3.41-3.50 (m, 4H), 3.70 (s, 3H), 4.00 (s, 2H), 4.07 (d, J=6.32 Hz, 2H),6.73-6.80 (m, 2H), 6.85-6.92 (m, 1H), 7.14-7.36 (m, 6H).

Example 1.39: Preparation of Sodium2-(((1s,4s)-4-((5-(2-Hydroxyethyl)-4-(3-methoxyphenyl-)-3-phenylpyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

2-(((1s,4s)-4-((5-(2-Hydroxyethyl)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid (8.2 mg, 0.017 mmol) was dissolved in ACN (0.2 mL). NaOH (5.71 μL,0.017 mmol) was added, followed by H₂O (0.2 mL), and the reaction wasstirred for an hour. After this time, the reaction was frozen andlyophilized to give the title compound (8.5 mg) as a white solid. LCMSm/z=479.4 [M−Na+H]⁺.

Example 1.40: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-5-(2-hydroxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 253)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-hydroxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand 2,3-difluorophenylboronic acid, using a similar method to the onedescribed in Example 1.37, the title compound was obtained as a whitesolid.

LCMS m/z=485.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.55 (m,8H), 1.73-1.83 (m, 1H), 2.09-2.19 (m, 1H), 2.73 (t, J=7.01 Hz, 2H),3.37-3.45 (m, 4H), 4.00 (s, 2H), 4.10 (d, J=7.45 Hz, 2H), 7.10-7.17 (m,1H), 7.19-7.32 (m, 6H), 7.38-7.49 (m, 1H).

Example 1.41: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-5-(2-hydroxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 254)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-hydroxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand 3-fluorophenylboronic acid, using a similar method to the onedescribed in Example 1.37, the title compound was obtained as a whitesolid. LCMS m/z=467.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.59(m, 8H), 1.77 (dd, J=9.92, 4.48 Hz, 1H), 2.09-2.19 (m, 1H), 2.77 (t,J=7.01 Hz, 2H), 3.41-3.48 (m, 4H), 4.00 (s, 2H), 4.08 (d, J=7.45 Hz,2H), 6.99-7.08 (m, 2H), 7.10-7.18 (m, 1H), 7.18-7.32 (m, 5H), 7.35-7.45(m, 1H).

Example 1.42: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-5-(2-hydroxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 276)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-hydroxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand 3-chloro-2-fluorophenylboronic acid, using a similar method to theone described in Example 1.37, the title compound was obtained as awhite solid.

LCMS m/z=501.5 [M+H]⁺.

Example 1.43: Preparation of2-(((1s,4s)-4-((5-(3-Hydroxypropyl)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 271) Step A: Preparation of5-(But-3-enyl)-3-phenyl-1H-pyrazole

Acetophenone (4.92 mL, 42.2 mmol) was dissolved in toluene (50 mL). Thereaction was cooled on an ice bath. LiHMDS (42.2 mL, 42.2 mmol) wasadded via syringe and the reaction was stirred for 2 min. Pent-4-enoylchloride (4.66 mL, 42.2 mmol) was added and then the reaction wasstirred for 2 more min. Hydrazine hydrate (8.18 mL, 169 mmol) was thenadded, along with AcOH (2 mL) and EtOH (2 mL). The reaction was warmedto room temperature and then heated in an oil bath to 80° C. for 1 h.After this time, the reaction was cooled and an extraction was performed(200 mL each of H₂O and EtOAc). The aqueous layer was extracted againwith EtOAc (200 mL). The combined organic layer was dried, concentrated,and the residue was purified by column chromatography to give the titlecompound (5.4 g) as a yellow oil. LCMS m/z=199.3 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.39 (q, J=7.28 Hz, 2H), 2.61-2.76 (m, 2H), 5.00 (d,J=9.98 Hz, 1H), 5.04-5.13 (m, 1H), 5.78-5.95 (m, 1H), 6.47 (s, 1H),7.21-7.33 (m, 1H), 7.33-7.48 (m, 2H), 7.65-7.81 (m, 2H), 12.56 (s, 1H).

Step B: Preparation of 3-(3-Phenyl-1H-pyrazol-5-yl)propan-1-ol

5-(But-3-enyl)-3-phenyl-1H-pyrazole (5.4 g, 27.2 mmol) was dissolved inMeOH (40 mL) and DCM (10 mL). The reaction was cooled on adry-ice/acetone bath and ozone was bubbled through the solution for ˜2h. The reaction was transferred into an ice bath and NaBH₄ (1.546 g,40.9 mmol) was added slowly portion-wise (bubbling was observed). Uponcomplete addition, the reaction was removed from the ice bath andstirred at room temperature for 1 h.

Excess solvent was evaporated and the reaction was extracted (100 mLeach of H₂O and EtOAc). The aqueous layer was extracted again with EtOAc(100 mL). The combined organic layer was dried, concentrated, and theresidue was purified by column chromatography to yield the titlecompound (3.0 g) as a white solid. LCMS m/z=203.3 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.72-1.82 (m, 2H), 2.54-2.69 (m, 2H), 3.46 (q,J=6.11 Hz, 2H), 4.40-4.54 (m, 1H), 6.45 (s, 1H), 7.21-7.45 (m, 3H),7.66-7.79 (m, J=7.45 Hz, 2H), 12.53 (s, 1H).

Step C: Preparation of 3-(4-Bromo-3-phenyl-1H-pyrazol-5-yl)propan-1-ol

3-(3-Phenyl-1H-pyrazol-5-yl)propan-1-ol (3.0 g, 14.83 mmol) wasdissolved in dry DCM (40 mL) and THF (15 mL). The reaction was cooled inan ice bath and Br₂ (1.146 mL, 22.25 mmol) pre-dissolved in DCM (10 mL)was added slowly dropwise via addition funnel. The reaction was stirredfor 2 h in an ice bath. The reaction was quenched by the addition ofNa₂SO₃ (20 mL of 10% solution; the reaction went from reddish-brown toclear and some bubbling was observed). The reaction was extracted (100mL each of H₂O and DCM). The aqueous layer was extracted again with DCM(100 mL). The combined organic layer was back extracted again with H₂O(200 mL). The organic layer was dried and concentrated to give the titlecompound (4.08 g) as a yellow solid. LCMS m/z=281.3 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.72-1.83 (m, 2H), 2.61-2.68 (m, 2H), 3.47 (t,J=6.44 Hz, 2H), 7.39 (t, J=7.33 Hz, 1H), 7.47 (t, J=7.45 Hz, 2H), 7.78(d, J=7.07 Hz, 2H).

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-(3-hydroxypropyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

3-(4-Bromo-3-phenyl-1H-pyrazol-5-yl)propan-1-ol, tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (2.93 g, 7.11mmol), and cesium carbonate (4.64 g, 14.23 mmol) were dissolved in DMF(35 mL). The reaction was heated to 80° C. in an oil bath and stirred atthis temperature for an hour. The reaction was cooled and extracted (100mL each of H₂O and EtOAc). The aqueous layer was extracted again withEtOAc (100 mL). The combined organic layer was back extracted once withH₂O (200 mL). The organic layer was dried, concentrated, and the residuewas purified by column chromatography to give the title compound (1.54g) as a light yellow oil. LCMS m/z=521.7 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.97-1.05 (m, 4H), 1.26-1.55 (m, 13H), 1.65-1.79 (m, 3H),2.01-2.12 (m, 1H), 2.71-2.77 (m, 2H), 3.39 (d, J=6.95 Hz, 2H), 3.46 (t,J=6.19 Hz, 2H), 3.94 (s, 2H), 4.06 (d, J=7.45 Hz, 2H), 7.32-7.39 (m,1H), 7.40-7.48 (m, 2H), 7.77-7.82 (m, J=8.34, 1.14 Hz, 2H).

Step E: Preparation of2-(((1s,4s)-4-((5-(3-Hydroxypropyl)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

tert-Butyl2-(((1s,4s)-4-((4-bromo-5-(3-hydroxypropyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(50 mg, 0.096 mmol), phenylboronic acid (1.1 eq),tetrakis(triphenylphosphine)palladium(0) (11.08 mg, 9.59 μmol), andK₂CO₃ (26.5 mg, 0.192 mmol) were added to a vial with dioxane (0.4 mL).The reaction was heated in a microwave at 150° C. for 2 h. After thistime, the reaction was filtered through a plug of MgSO₄. The solvent wasremoved and the ester intermediate obtained was re-dissolved in HCl (4Min dioxane) (503 μL, 2.013 mmol). The reaction was stirred overnight atroom temperature. The next day, the solvent was removed and the residuewas purified by preparative LC/MS. After lyophilizing the reaction,there was observed the side-product formation of the TFA-ester off ofthe side chain alcohol. Therefore, the product was dissolved in THF (0.3mL). Then 3M LiOH (50 μL) was added. The reactions were stirred at roomtemperature overnight. The next day, 1 M HCl (200 μL) was added to makethe reaction acidic. The reactions were extracted (2 mL each of HCl/H₂Oand EtOAc). The aqueous layer was extracted again with EtOAc (2 mL). Thecombined organic layer was dried and concentrated. The resulting oil wasre-dissolved in ACN (0.3 mL) and H₂O (0.2 mL). The mixture was frozenand lyophilized to give the title compound (8.9 mg) as a white solid.LCMS m/z=463.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.60 (m,10H), 1.71-1.84 (m, 1H), 2.08-2.19 (m, 1H), 2.59-2.65 (m, 2H), 3.31 (t,J=6.19 Hz, 2H), 3.43-3.44 (m, 2H), 3.99 (s, 2H), 4.05 (d, J=7.33 Hz,2H), 7.14-7.25 (m, 5H), 7.26-7.40 (m, 5H).

Example 1.44: Preparation of2-(((1s,4s)-4-((5-(3-Hydroxypropyl)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 272)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(3-hydroxypropyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand 3-methoxyphenylboronic acid, using a similar method to the onedescribed in Example 1.43, the title compound was obtained as a whitesolid.

LCMS m/z=493.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.61 (m,10H), 1.72-1.83 (m, 1H), 2.08-2.18 (m, 1H), 2.60-2.66 (m, 2H), 3.33 (t,J=6.19 Hz, 2H), 3.42 (d, J=6.82 Hz, 2H), 3.70 (s, 3H), 3.99 (s, 2H),4.04 (d, J=7.33 Hz, 2H), 6.70-6.75 (m, 2H), 6.87 (dd, J=7.96, 2.15 Hz,1H), 7.16-7.37 (m, 6H).

Example 1.45: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-5-(3-hydroxypropyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 273)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(3-hydroxypropyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand 2,3-difluorophenylboronic acid, using a similar method to the onedescribed in Example 1.43, the title compound was obtained as a whitesolid.

LCMS m/z=499.7 [M+H]⁺.

Example 1.46: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-5-(3-hydroxypropyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 274)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(3-hydroxypropyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand 3-fluorophenylboronic acid, using a similar method to the onedescribed in Example 1.43, the title compound was obtained as a whitesolid. LCMS m/z=481.3 [M+H]⁺.

Example 1.47: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-5-(3-hydroxypropyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 281)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(3-hydroxypropyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand 3-chloro-2-fluorophenylboronic acid, using a similar method to theone described in Example 1.43, the title compound was obtained as awhite solid.

LCMS m/z=515.5 [M+H]⁺.

Example 1.48: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-(3-hydroxypropyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 282)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(3-hydroxypropyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand 3-chlorophenylboronic acid, using a similar method to the onedescribed in Example 1.43, the title compound was obtained as a whitesolid. LCMS m/z=497.5 [M+H]⁺.

Example 1.49: Preparation of2-(((1s,4s)-4-((5-(3-hydroxypropyl)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 288) Step A: Preparation of5-(But-3-enyl)-4-phenyl-3-p-tolyl-1H-pyrazole

2-Phenyl-1-p-tolylethanone (1.0 g, 4.76 mmol) was dissolved in Toluene(20 mL). The reaction was cooled in an ice bath and then LiHMDS (4.76mL, 4.76 mmol) was added slowly via syringe. The reaction was stirred atthis temperature for 5 min and then pent-4-enoyl chloride (0.564 g, 4.76mmol) was added. The reaction was warmed to room temperature and stirredat this temperature for 20 min. After this time EtOH (10 mL), AcOH (2mL), and hydrazine hydrate (0.231 mL, 4.76 mmol) were added to thereaction. The reaction was heated to 80° C. and stirred at thistemperature for an hour. After this time, the reaction was cooled andextracted (50 mL each of EtOAc and IM NaOH). The aqueous layer wasextracted again with EtOAc (50 mL). The combined organic layer wasdried, concentrated, and the residue was purified by silica gel columnchromatography to give the title compound (355 mg) as a colorless oil.LCMS m/z=289.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) b ppm 2.22-2.32 (m,5H), 2.55-2.69 (m, 2H), 4.86-5.02 (m, 2H), 5.75 (s, 1H), 6.99-7.24 (m,6H), 7.25-7.31 (m, 1H), 7.33-7.39 (m, 2H), 12.74 (s, 1H).

Step B: Preparation of 3-(4-Phenyl-3-p-tolyl-1H-pyrazol-5-yl)propan-1-ol

5-(But-3-enyl)-4-phenyl-3-p-tolyl-1H-pyrazole (360 mg, 1.248 mmol) wasdissolved in MeOH (20 mL) and DCM (5 mL). The reaction was cooled to−78° C. and ozone was bubbled through the solution. After the startingmaterial was consumed, the reaction was cooled in an ice bath. Sodiumborohydride (70.8 mg, 1.872 mmol) was added to the reaction. Thereaction was warmed to room temperature and stirred for an hour. Thesolvent was removed under reduced pressure and the reaction wasextracted (50 mL each of H₂O and EtOAc). The aqueous layer was extractedagain with EtOAc (50 mL). The combined organic layer was dried,concentrated, and the residue was purified by silica gel columnchromatography to give the title compound (130 mg) as a white solid.LCMS m/z=293.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60-1.74 (m,2H), 2.25 (s, 3H), 2.54-2.62 (m, 2H), 3.33-3.44 (m, 2H), 4.44 (br. s.,1H), 7.16 (t, J=6.44 Hz, 6H), 7.24-7.30 (m, 1H), 7.32-7.38 (m, 2H),12.71 (s, 1H).

Step C: Preparation of2-(((1s,4s)-4-((5-(3-Hydroxypropyl)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

3-(4-Phenyl-3-p-tolyl-1H-pyrazol-5-yl)propan-1-ol (50 mg, 0.171 mmol),tert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(70.5 mg, 0.171 mmol), and Cs₂CO₃ (11 mg, 0.342 mmol) were suspended inDMF (0.5 mL). The reaction was heated at 80° C. for an hour. The mixturewas cooled and extracted (2 mL each of H₂O and EtOAc). The aqueous layerwas extracted again with EtOAc (2 mL). The combined organic layer wasfiltered through a plug of MgSO₄. The solvents were removed, then theresulting oil was re-dissolved in HCl (4M in dioxane) (0.5 mL, 2.000mmol). The reaction was stirred at room temperature overnight. Themixture was purified by preparative LC/MS. After lyophilization, theproduct was re-dissolved in THF (0.3 mL) and stirred with IM NaOH (100μL) overnight. The reaction was then made acidic by addition of IM HCl(200 μL). The reaction was extracted (2 mL each of H₂O and EtOAc). Theaqueous layer was extracted again with EtOAc (2 mL). The combinedorganic layer was filtered through a plug of MgSO₄ and concentrated togive the title compound (3.5 mg), one of the two regioisomers, as acolorless oil. LCMS m/z=477.4 [M+H]⁺.

Example 1.50: Preparation of2-(((1s,4s)-4-((3-(3-Hydroxypropyl)-4-phenyl-5-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 289)

The title compound was isolated as one of the two regioisomers fromExample 1.49, Step C, to give an oil. LCMS m/z=477.5 [M+H]⁺.

Example 1.51: Preparation of2-(((1s,4s)-4-((5-(2-fluoro-4-methylphenyl)-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 286) Step A: Preparation of tert-Butyl2-(((1s,4s)-4-((5-(2-Fluoro-4-methylphenyl)-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

3-(2-Fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazole (2.82 g, 10.59mmol) was dissolved in dry DMF (40 mL). Cs₂CO₃ (6.90 g, 21.18 mmol) andtert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(4.37 g, 10.59 mmol) were added. The reaction was heated to 80° C. andstirred at this temperature for 1 h. The reaction was cooled andextracted (100 mL each of H₂O and EtOAc). The aqueous layer wasextracted again with EtOAc (100 mL). The combined organic layer was backextracted once with H₂O/Brine (200 mL). The organic layer was dried,concentrated, and the residue was purified by chromatography to give thetitle compound (3.2 g), a mixture of regioisomers, as a colorless oil.LCMS m/z=507.2 [M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((5-(2-Fluoro-4-methylphenyl)-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

tert-Butyl2-(((1s,4s)-4-((3-(2-fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(3.2 g, 6.32 mmol) was dissolved in HCl (4M in dioxane) (50.0 mL, 200mmol). The reaction was stirred overnight at room temperature. Thesolvent was removed and the residue was purified by HPLC to give thetitle compound as a colorless oil (746 mg). LCMS m/z=451.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.08-1.20 (m, 4H), 1.22-1.37 (m, 4H),1.57-1.69 (m, 1H), 1.90-1.97 (m, 1H), 2.23 (s, 3H), 2.35 (s, 3H), 3.22(d, J=6.82 Hz, 2H), 3.71-3.87 (m, 2H), 3.92 (s, 2H), 7.04-7.11 (m, 4H),7.11-7.20 (m, 2H), 7.24 (t, J=7.33 Hz, 2H).

Example 1.52: Preparation of2-(((1s,4s)-4-((3-(4-Chlorophenyl)-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 163) Step A: Preparation of1-(Dimethylamino)-2-phenylpent-1-en-3-one

To a solution of 1-phenylbutan-2-one (5.00 g, 33.7 mmol) in DMF (80.0mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (6.03 g, 50.6 mmol).The resulting mixture was stirred at 90° C. for 16 h. Upon completion,the reaction mixture was quenched with water (40.0 mL), extracted withEtOAc (4×50.0 mL), and washed with brine. The combined organics weredried over MgSO₄, filtered, and concentrated to give a brown oil. Thisbrown oil was purified by flash chromatography to give the titlecompound as a yellow oil (3.32 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.97(t, J=7.32 Hz, 3H), 2.19 (q, J=7.49 Hz, 2H), 2.67 (s, 6H), 7.14-7.41 (m,5H), 7.61 (s, 1H).

Step B: Preparation of 5-Ethyl-4-phenyl-1H-pyrazole

To a mixture of 1-(dimethylamino)-2-phenylpent-1-en-3-one (3.32 g, 16.33mmol) in EtOH (80.0 mL) was added hydrazine hydrate (1.58 mL, 32.66mmol). The resulting mixture was stirred at 80° C. for 3 h. The reactionmixture was cooled to room temperature and concentrated to give a solid.The solid was re-crystallized, using 20% ethanol in water to give thetitle compound as a white solid (2.81 g). LCMS m/z=173 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 1.31 (t, J=7.58 Hz, 3H), 2.88 (q, J=7.58 Hz, 2H),7.22-7.30 (m, 1H), 7.35-7.42 (m, 4H).

Step C: Preparation of 3-Bromo-5-ethyl-4-phenyl-1H-pyrazole

To a solution of 5-ethyl-4-phenyl-1H-pyrazole (3.34 g, 19.39 mmol) indichloromethane (111.0 mL), was added bromine (1.49 mL, 29.09 mmol) at25° C. The reaction was stirred at room temperature for 72 h andquenched with NaOH (aq.) to pH 12. The organics were separated. Theaqueous layer was extracted again with DCM (3×). The combined organicswere washed with brine, dried (MgSO₄), filtered and concentrated to givea red oil. This oil was purified by flash chromatography to give thetitle compound as a yellow oil (2.84 g). LCMS m/z=251.2 [M+H]⁺.

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-((3-Bromo-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 3-bromo-5-ethyl-4-phenyl-1H-pyrazole (0.364 g, 1.451mmol) in DMF (5.0 mL), was slowly added 60% sodium hydride (0.070 g,1.740 nmmol). The solution was allowed to stir for a total of 20 min,before a mixture of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (0.598 g, 1.450mmol) in DMF (1.0 mL) was' added. The reaction mixture was then stirredat 45° C. for 12 h. Upon completion, the reaction mixture was quenchedwith water and extracted with EtOAc (4×). The combined organics weredried over MgSO₄, filtered, and concentrated to give a brown oil. Thisbrown oil was purified by flash chromatography to give the titlecompound as a yellow oil (0.213 g). LCMS m/z=491.4, 493.5 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 1.13-1.29 (m, 4H), 1.27-1.41 (m, 2H), 1.43-1.62(m, 13H), 1.79-1.93 (m, 2H), 2.09-2.25 (m, 1H), 2.76 (q, J=7.58 Hz, 2H),3.39-3.50 (m, 2H), 3.84-4.05 (m, 4H), 7.20-7.28 (m, 2H), 7.33-7.39 (m,1H), 7.45-7.54 (m, 2H) Step E: Preparation of tert-Butyl2-(((1s,4s)-4-((3-(4-Chlorophenyl)-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate.

To a solution of 4-chlorophenylboronic acid (0.019 g, 0.122 mmol),tert-butyl2-(((1s,4s)-4-((3-bromo-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(0.060 g, 0.122 mmol), tetrakis(triphenylphosphine)palladium (0) (0.004g, 0.004 mmol) in benzene (3.0 mL) and EtOH (1.0 mL) was added sodiumcarbonate (0.122 mL, 0.244 mmol). The reaction mixture was then heatedin a microwave at 130° C. for 1 h. Upon completion, the reaction mixturewas diluted with water and extracted with EtOAc (3×). The combinedorganics were dried over MgSO₄, filtered, and concentrated to give ayellow oil. This yellow oil was re-suspended in ACN/H₂O and purified byHPLC to give the title compound as a white solid (0.032 g). LCMSm/z=523.4, 525.8 [M+H]⁺.

Step F: Preparation of2-(((1s,4s)-4-((3-(4-Chlorophenyl)-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((3-(4-chlorophenyl)-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(0.032 g, 0.060 mmol) in DCM (2.0 mL) was added 4M HCl in dioxane (0.151mL, 0.602 mmol). The resulting reaction mixture was stirred at 25° C.for 16 h. The reaction was concentrated to give a yellow oil. Thisyellow oil was then re-suspended in ACN/H₂O and purified by HPLC to givethe title compound as a white solid (0.004 g). LCMS m/z=467.5 [M+H]⁺.

Example 1.53: Preparation of2-(((1s,4s)-4-((3-(3,4-difluorophenyl)-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 284) Step A: Preparation of tert-Butyl2-(((1s,4s)-4-((3-(3,4-Difluorophenyl)-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

From 3,4-difluorophenylboronic acid and tert-butyl2-(((1s,4s)-4-((3-bromo-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.52, Step E, thetitle compound was obtained as a white solid. LCMS m/z=525.5 [M+H]⁺.

Step B:2-(((1s,4s)-4-((3-(3,4-Difluorophenyl)-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1s,4s)-4-((3-(3,4-difluorophenyl)-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.52, Step F, thetitle compound was obtained as a white solid. LCMS m/z=469.5 [M+H]⁺.

Example 1.54: Preparation of2-(((1s,4s)-4-((5-Ethyl-3-(4-fluorophenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 164) Step A: Preparation of tert-Butyl2-(((1s,4s)-4-((5-Ethyl-3-(4-fluorophenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

From 4-difluorophenylboronic acid and tert-butyl2-(((1s,4s)-4-((3-bromo-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.52, Step E, thetitle compound was obtained as a white solid. LCMS m/z=507.4 [M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((5-Ethyl-3-(4-fluorophenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1s,4s)-4-((5-ethyl-3-(4-fluorophenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.52, Step F, thetitle compound was obtained as a white solid. LCMS m/z=451.3 [M+H]⁺.

Example 1.55: Preparation of2-(((1s,4s)-4-((5-Ethyl-3-(2-fluoro-4-methoxyphenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 165) Step A: Preparation of tert-Butyl2-(((1s,4s)-4-((5-Ethyl-3-(2-fluoro-4-methoxyphenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 2-fluoro-4-methoxyphenylboronic acid (0.021 g, 0.122mmol), tert-butyl2-(((1s,4s)-4-((3-bromo-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(0.060 g, 0.122 mmol), aq. Na₂CO₃ (2 M solution, 0.122 mL, 0.244 mmol),and Pd(PPh₃)₄(0.004 g, 0.004 mmol) in EtOH (1.0 mL) and benzene (3.0mL). The reaction mixture was then heated in a microwave at 130° C. for1 h. Upon completion, the reaction mixture was quenched with H₂O andextracted with EtOAc (2×). The combined organics layers were dried overMgSO₄, filtered and concentrated to give the title compound as a yellowoil without further purification. LCMS m/z=537.5 [M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((5-Ethyl-3-(2-fluoro-4-methoxyphenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To tert-butyl2-(((1s,4s)-4-((5-ethyl-3-(2-fluoro-4-methoxyphenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateobtained was added 4 M HCl (0.610 mL, 2.44 mmol) in 1,4-dioxane. Thereaction mixture was stirred at 40° C. for 6 h. The reaction mixture wasconcentrated and the residue was purified by HPLC to give the titlecompound (0.005 g) as a white solid. LCMS m/z=481.2 [M+H]⁺.

Example 1.56: Preparation of2-(((1s,4s)-4-((5-Ethyl-3-(4-methoxyphenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 166)

From 4-methoxyphenylboronic acid and tert-butyl2-(((1s,4s)-4-((3-bromo-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.55, the titlecompound was obtained as a white solid. LCMS m/z=463.4 [M+H]⁺.

Example 1.57: Preparation of2-(((1s,4s)-4-((5-Ethyl-3-(2-fluoro-4-methylphenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 167)

From 2-fluoro-4-methylphenylboronic acid and tert-butyl2-(((1s,4s)-4-((3-bromo-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.55, the titlecompound was obtained as a white solid. LCMS m/z=465.2 [M+H]⁺.

Example 1.58: Preparation of2-(((1s,4s)-4-((5-Ethyl-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 168)

From p-tolylboronic acid and tert-butyl2-(((1s,4s)-4-((3-bromo-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.55, the titlecompound was obtained as a white solid. LCMS m/z=447.5 [M+H]⁺.

Example 1.59: Preparation of2-(((1s,4s)-4-((5-Ethyl-3-(4-hydroxyphenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 175)

From 4-hydroxyphenylboronic acid and tert-butyl2-(((1s,4s)-4-((3-bromo-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.55, The titlecompound was obtained as a white solid. LCMS m/z=449.3 [M+H]⁺.

Example 1.60: Preparation of2-(((1s,4s)-4-((3-(4-Chloro-3-fluorophenyl)-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 176)

From 4-chloro-3-fluorophenylboronic acid and tert-butyl2-(((1s,4s)-4-((3-bromo-5-ethyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.55, The titlecompound was obtained as a white solid. LCMS m/z=485.4 [M+H]⁺.

Example 1.61: Preparation of2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 202) Step A: Preparation of 3-Phenyl-5-propyl-1H-pyrazole

To a solution of acetophenone (4.87 mL, 41.6 mmol) in dry toluene (5.0mL) cooled to 0° C. was added LiHMDS (41.6 mL, 41.6 mmol). The resultingmixture was stirred at 0° C. for 5 min before butyryl chloride (4.36 mL,41.6 mmol) was added in portions. After the addition of the butyrylchloride, the ice bath was then removed before AcOH (2.0 mL) and EtOH(10.0 mL) were added to form a homogenous mixture, then hydrazinehydrate (3.03 mL, 62.4 mmol) was added. The resulting mixture was heatedto reflux. After 30 min, the reaction mixture was quenched with 1.0 MNaOH solution, extracted with EtOAc and washed with brine. The combinedorganics were dried over MgSO₄, filtered, and concentrated to give anorange oil. This orange oil was purified by silica gel flashchromatography to give the title compound as a yellow oil (3.83 g). LCMSm/z=187.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.92 (t, J=7.33 Hz, 3H),1.58-1.71 (m, 2H), 2.57 (t, J=7.58 Hz, 2H), 6.34 (s, 1H), 7.22-7.39 (m,3H), 7.72 (d, J=7.83 Hz, 2H).

Step B: Preparation of 4-Bromo-3-phenyl-5-propyl-1H-pyrazole

To a solution of 3-phenyl-5-propyl-1H-pyrazole (3.83 g, 20.56 mmol) indichloromethane (118.0 mL) was added bromine (1.05 mL, 20.56 mmol) at25° C. The reaction mixture was stirred at room temperature for 16 h.The reaction mixture was then quenched with 2 M Na₂CO₃ (aq.) to pH 12and the organics were separated. The aqueous layer was extracted withDCM (thrice). The combined organics were washed with brine, dried overMgSO₄, filtered and concentrated to give a red oil. This oil waspurified by silica gel flash chromatography to give the title compoundas a yellow oil (3.44 g). LCMS m/z=265.1, 267.1 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 0.97 (t, J=7.33 Hz, 3H), 1.63-1.74 (m, 2H), 2.57 (t, J=7.58Hz, 2H), 7.37-7.48 (m, 3H), 7.77-7.82 (m, 2H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 4-bromo-3-phenyl-5-propyl-1H-pyrazole (1.00 g, 3.77mmol) in DMF (13.0 mL) was slowly added 60% sodium hydride (0.181 g,4.53 mmol). The solution was allowed to stir for a total of 20 min,before a mixture of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (1.556 g, 3.77mmol) in DMF (2.0 mL) was added. The reaction mixture was then stirredat 45° C. for 12 h, quenched with water and extracted with EtOAc (4times). The combined organics were dried over MgSO₄, filtered, andconcentrated to give a brown oil. This brown oil was purified by silicagel flash chromatography to give the title compound as a yellow oil(1.501 g). LCMS m/z=505.4, 507.4 [M+HJ]; ¹H NMR (400 MHz, CDCl₃) δ ppm1.02 (t, J=7.45 Hz, 3H), 1.29-1.41 (m, 2H), 1.43-1.59 (m, 15H), 1.65 (d,J=7.83 Hz, 2H), 1.82-1.94 (m, 1H), 2.13-2.24 (m, 1H), 2.66 (t, J=7.83Hz, 2H), 3.46 (d, J=7.07 Hz, 2H), 3.95 (s, 2H), 4.00 (d, J=7.58 Hz, 2H),7.33 (d, J=7.58 Hz, 1H), 7.40 (t, J=7.45 Hz, 2H), 7.84-7.89 (m, 2H).

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 3-methoxyphenylboronic acid (0.029 g, 0.194 mmol),tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(0.098 g, 0.194 mmol), aq. Na₂CO₃ (2 M solution, 0.194 mL, 0.388 mmol),and Pd(PPh₃)₄ (0.004 g, 0.007 mmol) in EtOH (1.0 mL) and benzene (3.0mL). The reaction mixture was then heated in a microwave at 130° C. for1 h, quenched with H₂O and extracted with EtOAc (2×).

The combined organics layers were dried over MgSO₄, filtered andconcentrated to give the title compound as a yellow oil withoutpurification. LCMS m/z=533.4 [M+H]⁺.

Step E: Preparation of2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To tert-butyl2-(((1s,4s)-4-((4-(3-methoxyphenyl)-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateobtained was added 4 M HCl (0.969 mL, 3.88 mmol) in 1,4-dioxane. Theresulting reaction mixture was stirred at 25° C. for 4 h. The reactionwas concentrated to give a yellow oil. This yellow oil was purified byHPLC to give the title compound (0.026 g) as a white solid. LCMSm/z=477.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.87 (t, J=7.33 Hz, 3H),1.33-1.62 (m, 9H), 1.86-1.97 (m, 1H), 2.17-2.29 (m, 1H), 2.54-2.62 (m,2H), 3.50-3.55 (m, 2H), 3.72 (s, 3H), 3.86 (s, 1H), 4.02-4.13 (m, 4H),6.70-6.86 (m, 3H), 7.15-7.27 (m, 4H), 7.34-7.43 (m, 2H).

Example 1.62: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-3-phenyl-5-propyl-1H-pyrazol-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 203)

From 3-fluorophenylboronic acid tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.61, Step D & E,the title compound was obtained as a white solid.

LCMS m/z=465.2 [M+H]⁺.

Example 1.63: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 204)

From 3-chlorophenylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.62, the titlecompound was obtained as a white solid. LCMS m/z=481.3 [M+H]⁺.

Example 1.64: Preparation of2-(((1s,4s)-4-((3-Phenyl-5-propyl-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 205)

From m-tolylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.62, the titlecompound was obtained as a white solid. LCMS m/z=461.5 [M+H]⁺.

Example 1.65: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-3-methoxyphenyl)-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 206)

From 2-fluoro-3-methoxyphenylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.62, the titlecompound was obtained as a white solid. LCMS m/z=495.5 [M+H]⁺.

Example 1.66: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 207)

From 2,3-difluorophenylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.62, the titlecompound was obtained as a white solid. LCMS m/z=483.4 [M+H]⁺.

Example 1.67: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 208)

From 3-chloro-2-fluorophenylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.62, the titlecompound was obtained as a white solid. LCMS m/z=499.7 [M+H]⁺.

Example 1.68: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-3-methylphenyl)-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 209)

From 2-fluoro-3-methylphenylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.62, the titlecompound was obtained as a white solid. LCMS m/z=479.6 [M+H]⁺.

Example 1.69: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-3-hydroxyphenyl)-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 211)

From 2-fluoro-3-hydroxyphenylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.62, the titlecompound was obtained as a white solid. LCMS m/z=481.3 [M+H]⁺.

Example 1.70: Preparation of2-(((1s,4s)-4-((5-(4-Fluorophenyl)-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 223) Step A: Preparation of1-(Dimethylamino)-2-phenylhex-1-en-3-one

To a solution of 1-phenylpentan-2-one (5.00 g, 30.8 mmol) in dry DMF(80.0 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (6.16 mL, 46.2mmol). The resulting mixture was heated at 90° C. After 16 h, thereaction mixture was quenched with water, extracted with EtOAc (3×) andwashed with brine. The combined organics were dried over MgSO₄,filtered, and concentrated to give a yellow oil. This yellow oil waspurified by silica gel flash chromatography to give the title compoundas a yellow oil (3.51 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.76-0.83 (m,3H), 0.83-0.89 (m, 2H), 2.11-2.19 (m, 2H), 2.62-2.71 (m, 6H), 7.15-7.42(m, 5H), 7.61 (s, 1H).

Step B: Preparation of 4-Phenyl-5-propyl-1H-pyrazole

To a solution of 1-(dimethylamino)-2-phenylhex-1-en-3-one (3.51 g, 16.2mmol) in ethanol (80.0 mL), was added hydrazine hydrate (1.57 mL, 32.4mmol). The reaction mixture was stirred at 80° C. After 3 h, thereaction mixture was cooled to room temperature, concentrated underreduced pressure and crystallized in 20% ethanol/H₂O to give the titlecompound as a white solid (3.01 g).

LCMS m/z=187.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.92-1.00 (m, 3H),1.64-1.76 (m, 2H), 2.75-2.84 (m, 2H), 7.36-7.41 (m, 5H), 7.65 (s, 1H).

Step C: Preparation of 3-Bromo-4-phenyl-5-propyl-1H-pyrazole

To a solution of 4-phenyl-5-propyl-1H-pyrazole (1.43 g, 7.68 mmol) inacetonitrile (38.0 mL), was added N-bromosuccinimide (1.50 g, 8.45mmol). The reaction mixture was stirred at 82° C. After 16 h, thereaction mixture was quenched with 2 M Na₂CO₃ (aq.) to pH 12 and theorganics were separated. The aqueous layer was extracted with EtOAc(3×). The combined organics were dried over MgSO₄, filtered andconcentrated to give a dark oil. This oil was purified by silica gelflash chromatography to give the title compound as a yellow oil (0.310g). LCMS m/z=265.1, 267.1 [M+H]⁺.

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-((3-Bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((5-Bromo-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 3-bromo-4-phenyl-5-propyl-1H-pyrazole (0.940 g, 3.55mmol) in DMF (12.0 mL), was slowly added 60% sodium hydride (0.170 g,4.25 mmol). The solution was stirred for a total of 20 min, before amixture of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (1.463 g, 3.55mmol) in DMF (2.0 mL) was added. The reaction mixture was then stirredat 45° C. for 12 h, quenched with water and extracted with EtOAc (4×).The combined organics were dried over MgSO₄, filtered, and concentratedto give a brown oil. This brown oil was purified by silica gel flashchromatography to give a mixture of regioisomers, the title compounds asa yellow oil (1.219 g). LCMS m/z=505.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δppm 0.85 (t, J=7.33 Hz, 3H), 1.32-1.63 (m, 18H), 1.76-1.93 (m, 2H),2.17-2.29 (m, 1H), 2.56-2.64 (m, 2H), 3.45 (d, J=6.82 Hz, 2H), 3.95 (s,2H), 4.05-4.14 (m, 2H), 7.28-7.35 (m, 3H), 7.36-7.43 (m, 2H).

Step E: Preparation of tert-Butyl2-(((1s,4s)-4-((5-(4-Fluorophenyl)-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((3-(4-Fluorophenyl)-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 4-fluorophenylboronic acid (0.032 g, 0.231 mmol), amixture of regioisomers, tert-butyl2-(((1s,4s)-4-((3-bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(0.117 g, 0.231 mmol), aq. Na₂CO₃ (2 M solution, 0.231 mL, 0.463 mmol),and Pd(PPh₃)₄(0.008 g, 0.007 mmol) in EtOH (1.0 mL) and benzene (3.0mL). The reaction mixture was then heated under microwave at 130° C. for1 h, quenched with H₂O and extracted with EtOAc (2×). The combinedorganics layers were dried over MgSO₄, filtered and concentrated to givea mixture of regioisomers, the title compounds as a yellow oil withoutfurther purification. LCMS m/z=521.7 [M+H]⁺.

Step F: Preparation of2-(((1s,4s)-4-((5-(4-Fluorophenyl)-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a mixture of regioisomers, tert-Butyl2-(((1s,4s)-4-((5-(4-Fluorophenyl)-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((3-(4-Fluorophenyl)-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateobtained was added 4 M HCl (1.16 mL, 4.63 mmol) in 1,4-dioxane. Theresulting reaction mixture was stirred at 25°. After 4 h, the reactionmixture concentrated to give a yellow oil. This yellow oil was purifiedby HPLC to give the title compound (0.019 g) as a white solid. LCMSm/z=465.3 [M+H]⁺.

Example 1.71: Preparation of2-(((1s,4s)-4-((3-(4-Fluorophenyl)-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 224)

From a mixture of regioisomers, tert-butyl2-(((1s,4s)-4-((5-(4-fluorophenyl)-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-(4-fluorophenyl)-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.70, Step F, thetitle compound was obtained as a second isomer. LCMS m/z=465.3 [M+H]⁺;¹H NMR (400 MHz, CDCl₃) δ ppm 0.87 (t, J=7.26 Hz, 3H), 1.16-1.30 (m,1H), 1.33-1.68 (m, 8H), 1.94 (s, 2H), 2.21 (s, 1H), 2.52-2.64 (m, 2H),3.53 (d, J=6.95 Hz, 2H), 3.97-4.19 (m, 4H), 6.91 (t, J=8.72 Hz, 2H),7.13-7.19 (m, 2H), 7.28-7.39 (m, 5H).

Example 1.72: Preparation of2-(((1s,4s)-4-((5-(4-Chloro-3-fluorophenyl)-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 225)

From 4-chloro-3-fluorophenylboronic acid and a mixture of regioisomers,tert-butyl2-(((1s,4s)-4-((3-bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.70, Step E & F,the title compound was obtained as a white solid. LCMS m/z=499.6 [M+H]⁺.

Example 1.73: Preparation of2-(((1s,4s)-4-((3-(4-Chloro-3-fluorophenyl)-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 226)

From 4-chloro-3-fluorophenylboronic acid and a mixture of regioisomers,tert-butyl2-(((1s,4s)-4-((3-bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.72, the titlecompound was obtained as an isomer. LCMS m/z=499.7 [M+H]⁺.

Example 1.74: Preparation of2-(((1s,4s)-4-((5-(4-Chlorophenyl)-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 227)

From 4-chlorophenylboronic acid and a mixture of regioisomers,tert-butyl2-(((1s,4s)-4-((3-bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.72, the titlecompound was obtained as a white solid. LCMS m/z=481.2 [M+H]⁺.

Example 1.75: Preparation of2-(((1s,4s)-4-((3-(4-Chlorophenyl)-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 228)

From 4-chlorophenylboronic acid and a mixture of regioisomers,tert-butyl2-(((1s,4s)-4-((3-bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.72, the titlecompound was obtained as a white solid. LCMS m/z=481.4 [M+H]⁺.

Example 1.76: Preparation of2-(((1s,4s)-4-((5-(3,4-Difluorophenyl)-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 229)

From 3,4-difluorophenylboronic acid and a mixture of regioisomers,tert-butyl2-(((1s,4s)-4-((3-bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.72, the titlecompound was obtained as a white solid. LCMS m/z=483.4 [M+H]⁺.

Example 1.77: Preparation of2-(((1s,4s)-4-((3-(3,4-Difluorophenyl)-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 230)

From 3,4-difluorophenylboronic acid and a mixture of regioisomers,tert-butyl2-(((1s,4s)-4-((3-bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.72, the titlecompound was obtained as a white solid. LCMS m/z=483.4 [M+H]⁺.

Example 1.78: Preparation of2-(((1s,4s)-4-((5-(2-Fluoro-4-methoxyphenyl)-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 231)

From 2-fluoro-4-methoxyphenylboronic acid and a mixture of regioisomers,tert-butyl2-(((1s,4s)-4-((3-bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.72, the titlecompound was obtained as a white solid. LCMS m/z=495.6 [M+H]⁺.

Example 1.79: Preparation of2-(((1s,4s)-4-((3-(2-Fluoro-4-methoxyphenyl)-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 232)

From 2-fluoro-4-methoxyphenylboronic acid and a mixture of regioisomers,tert-butyl2-(((1s,4s)-4-((3-bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-4-phenyl-3-propyl-1H-pyrazol-t-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.72, the titlecompound was obtained as a white solid. LCMS m/z=495.5 [M+H]⁺.

Example 1.80: Preparation of2-(((1s,4s)-4-((5-(4-Methoxyphenyl)-4-phenyl-3-propyl-.If-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 233)

From 4-methoxyphenylboronic acid and a mixture of regioisomers,tert-butyl2-(((1s,4s)-4-((3-bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.72, the titlecompound was obtained as a white solid. LCMS m/z=477.4 [M+H].

Example 1.81: Preparation of2-(((1s,4s)-4-((3-(4-Methoxyphenyl)-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 234)

From 4-methoxyphenylboronic acid and a mixture of regioisomers,tert-butyl2-(((1s,4s)-4-((3-bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.72, the titlecompound was obtained as a white solid. LCMS m/z=477.5 [M+H]⁺.

Example 1.82: Preparation of2-(((1s,4s)-4-((5-(2-Fluoro-4-methylphenyl)-4-phenyl-3-propyl-1H-pyrazol-1-yl)methy)cyclohexyl)methoxy)aceticAcid (Compound 235)

From 2-fluoro-4-methylphenylboronic acid and a mixture of regioisomers,tert-butyl2-(((1s,4s)-4-((3-bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.72, the titlecompound was obtained as a white solid. LCMS m/z=479.5 [M+H]⁺.

Example 1.83: Preparation of2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 236)

From 2-fluoro-4-methylphenylboronic acid and a mixture of regioisomers,tert-butyl2-(((1s,4s)-4-((3-bromo-4-phenyl-5-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-4-phenyl-3-propyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.72, the titlecompound was obtained as a white solid. LCMS m/z=479.4 [M+H]⁺.

Example 1.84: Preparation of2-(((1s,4s)-4-((5-(Cyanomethylthio)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 257) Step A: Preparation of2-(1,3-Dithietan-2-ylidene)-2-phenyl-1-p-tolylethanone

To a solution of 2-phenyl-1-p-tolylethanone (3.00 g, 14.27 mmol) in THF(50.0 mL) was added KOtBu (30.0 mL, 30.0 mmol), CS₂ (0.862 mL, 14.27mmol) and dibromomethane (0.994 mL, 14.27 mmol). The reaction wasstirred at 25° C. for 12 h, quenched with water (40.0 mL) and extractedwith EtOAc (3×50.0 mL). The combined organics were dried over MgSO₄,filtered, and concentrated to give the title compound as a brown oilwithout further purification.

LCMS m/z=299.2 [M+H]⁺.

Step B: Preparation of A Mixture of4-Phenyl-3-p-tolyl-1H-pyrazole-5(4H)-thione and1,2-Bis(4-phenyl-3-p-tolyl-1H-pyrazol-5-yl)disulfane

To a solution of 2-(1,3-dithietan-2-ylidene)-2-phenyl-1-p-tolylethanonedissolved in isopropanol (25.0 mL) was added hydrazine (7.00 mL, 143.0mmol). The reaction was stirred at 100° C. for 16 h. After cooling toroom temperature, a precipitate was formed. The precipitate was filteredand washed with isopropanol and dried under reduced pressure to give thetitle compounds as a mixture of4-phenyl-3-p-tolyl-1H-pyrazole-5(4H)-thione and1,2-bis(4-phenyl-3-p-tolyl-1H-pyrazol-5-yl)disulfane as a white solid(2.24 g). LCMS m/z=267.2 [M+H]⁺; 531.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δppm 2.31 (s, 3H), 7.04 (d, J=7.58 Hz, 2H), 7.10-7.16 (m, 1H), 7.17-7.27(m, 5H), 7.39 (d, J=7.33 Hz, 2H).

Step C: Preparation of2-(4-Phenyl-3-p-tolyl-1H-pyrazol-5-ylthio)acetonitrile

To a mixture of 4-phenyl-3-p-tolyl-1H-pyrazole-5(4H)-thione and1,2-bis(4-phenyl-3-p-tolyl-1H-pyrazol-5-yl)disulfane (0.500 g, 1.88mmol) in DMF (12.5 mL) was added 2-bromoacetonitrile (0.125 mL, 1.88mmol) and K₂CO₃ (0.259 g, 1.88 mmol). The reaction was stirred at 25° C.for 72 h, quenched with water (40.0 mL) and extracted with EtOAc (4×50.0mL) and washed with brine. The combined organics were dried over MgSO₄,filtered, and concentrated to give the title compound as a yellow oil(0.547 g). LCMS m/z=306.2 [M+H]⁺.

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((5-(Cyanomethylthio)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 2-(4-phenyl-3-p-tolyl-1H-pyrazol-5-ylthio)acetonitrile(0.250 g, 0.819 mmol) in anhydrous DMF (4.0 mL) was added cesiumcarbonate (0.533 g, 1.64 mmol) and tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (0.338 g, 0.819mmol) in DMF (1.0 mL). The reaction was heated at 80° C. for 1 h,quenched with water and extracted with EtOAc (2×). The combined organicswere dried over MgSO₄, filtered, and concentrated to give the titlecompound as a yellow oil without further purification. LCMS m/z=546.4[M+H]⁺.

Step D: Preparation of2-(((1s,4s)-4-((5-(Cyanomethylthio)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To tert-butyl2-(((1s,4s)-4-((5-(cyanomethylthio)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateobtained above was added 4 M HCl (4.09 mL, 16.37 mmol) in 1,4-dioxane.The reaction was stirred at 25° C. for 16 h and concentrated to give ayellow oil. This yellow oil was purified by HPLC to give the titlecompound as a white solid (0.013 g). LCMS m/z=490.5 [M+H]⁺.

Example 1.85: Preparation of2-(((1r,4r)-4-((3-(Cyanomethylthio)-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 245) Step A: Preparation of2-(4-(3-Methoxyphenyl)-3-phenyl-1H-pyrazol-5-ylthio)acetonitrile

To a solution of 4-(3-methoxyphenyl)-3-phenyl-1H-pyrazole-5(4H)-thione(0.200 g, 0.708 mmol) in DMF (5.0 mL) was added 2-bromoacetonitrile(0.047 mL, 0.708 mmol) and K₂CO₃ (0.098 g, 0.708 mmol). The mixture wasstirred at 25° C. for 72 h, quenched with water (40.0 mL), extractedwith EtOAc (4×50.0 mL) and washed with brine. The combined organics weredried over MgSO₄, filtered, and concentrated to give a brown oil. Thisbrown oil was purified by silica gel flash chromatography to give thetitle compound as a white solid (0.158 g).

LCMS m/z=332.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.67 (s, 2H), 3.74(s, 3H), 6.82-6.89 (m, 3H), 7.23-7.29 (m, 1H), 7.34 (s, 5H).

Step B: Preparation of tert-Butyl2-(((1r,4r)-4-((3-(Cyanomethylthio)-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((5-(Cyanomethylthio)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of2-(4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-5-ylthio)acetonitrile (0.158g, 0.492 mmol) in DMF (2.0 mL) at 0° C. was slowly added 60% sodiumhydride (0.022 g, 0.541 mmol). The solution was allowed to stir for atotal of 20 min, before a mixture of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (0.203 g, 0.492mmol) in DMF (1.0 mL) was added. The reaction mixture was then stirredat 40° C. for 16 h, quenched with water and extracted with EtOAc (2×).The combined organics were dried over MgSO₄, filtered, and concentratedto give a mixture of tert-butyl2-(((1r,4r)-4-((3-(cyanomethylthio)-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-(cyanomethylthio)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetatewithout further purification. LCMS m/z=562.4 [M+H]⁺.

Step C: Preparation of2-(((1r,4r)-4-((3-(Cyanomethylthio)-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To the mixture of tert-butyl2-(((1r,4r)-4-((3-(cyanomethylthio)-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-(cyanomethylthio)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateobtained above was added 4 M HCl (2.46 mL, 9.83 mmol) in 1,4-dioxane.The reaction was stirred at 25° C. for 16 h and concentrated to give ayellow oil. This yellow oil was purified by HPLC to give the titlecompound (0.042 g) as a white solid. LCMS m/z=506.5 [M+H]⁺.

Example 1.86: Preparation of2-(((1s,4s)-4-((5-(Cyanomethylthio)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 246)

From a mixture of regioisomers tert-butyl2-(((1r,4r)-4-((3-(cyanomethylthio)-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-(cyanomethylthio)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.85, Step C, thetitle compound was also isolated as a white solid. LCMS m/z=506.4[M+H]⁺.

Example 1.87: Preparation of2-(((1s,4s)-4-((5-(Cyanomethylthio)-3-(4-fluorophenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 258)

From 1-(4-fluorophenyl)-2-phenylethanone, using a similar method to theone described in Example 1.85, the title compound was obtained as awhite solid. LCMS m/z=494.5 [M+H]⁺.

Example 1.88: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-(cyanomethylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 275)

From 2-(3-chlorophenyl)-1-phenylethanone, using a similar method to theone described in Example 1.85, the title compound was obtained as awhite solid. LCMS m/z=510.3 [M+H]⁺.

Example 1.89: Preparation of2-(((1r,4r)-4-((3-(2-Amino-2-oxoethoxy)-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 277) Step A: Preparation of2-(3-Phenyl-1H-pyrazol-5-yloxy)acetonitrile

To a solution of 3-phenyl-1H-pyrazol-5(4H)-one (1.00 g, 6.24 mmol) inDMF (5.0 mL) was added 2-bromoacetonitrile (0.520 mL, 7.80 mmol) andK₂CO₃ (0.863 g, 6.24 mmol). The reaction was stirred at 25° C. for 12 h,quenched with water (40.0 mL), extracted with EtOAc (3×50.0 mL) andwashed with brine. The combined organics were dried over MgSO₄,filtered, and concentrated to give the title compound as a yellow oil.This yellow oil was purified by silica gel flash chromatography to givethe title compound as a clear oil (0.990 g). LCMS m/z=200.3 [M+H]⁺.

Step B: Preparation of2-(4-Bromo-3-phenyl-1H-pyrazol-5-yloxy)acetonitrile

To a solution of 2-(3-phenyl-1H-pyrazol-5-yloxy)acetonitrile (0.500 g,2.51 mmol) in dichloromethane (15.0 mL), was added bromine (0.129 mL,2.51 mmol) at 25° C. The reaction was stirred at room temperature for 1h and quenched with 2 M Na₂CO₃ (aq.) to pH 12. The organics wereseparated. The aqueous layer was extracted with DCM (3×). The combinedorganics were washed with brine, dried (MgSO₄), filtered andconcentrated to give a red oil.

This oil was purified by silica gel flash chromatography to give thetitle compound as a yellow solid (0.360 g). LCMS m/z=278.1, 280.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 5.21 (s, 2H), 7.39-7.61 (m, 3H),7.70-7.77 (m, 2H), 13.04 (s, 1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-(cyanomethoxy)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-Bromo-3-(cyanomethoxy)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 2-(4-bromo-3-phenyl-1H-pyrazol-5-yloxy)acetonitrile(0.570 g, 2.50 mmol) in anhydrous DMF (18.0 mL) was added cesiumcarbonate (1.34 g, 4.10 mmol) and a mixture of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (0.846 g, 2.50mmol) in DMF (2.0 mL). The reaction was heated at 80° C. for 1 h,quenched with water and extracted with EtOAc (3×). The combined organicswere dried over MgSO₄, filtered, and concentrated to give a yellow oil.This oil was purified by silica gel flash chromatography to give thetitle compound as a clear oil (0.386 g). LCMS m/z=518.4, 520.5 [M+H]⁺;¹H NMR (400 MHz, CDCl₃) δ ppm 1.09-1.22 (m, 1H), 1.28-1.57 (m, 13H),1.61 (s, 1H), 1.69-1.91 (m, 2H), 1.95-2.08 (m, 1H), 2.45 (s, 2H), 3.26(d, J=6.82 Hz, 1H), 3.36 (d, J=6.82 Hz, 1H), 3.83-3.97 (m, 3H), 4.97 (d,2H), 7.31-7.38 (m, 2H), 7.45-7.51 (m, 1H), 7.78 (d, J=8.34 Hz, 2H).

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-((3-(Cyanomethoxy)-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((5-(Cyanomethoxy)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 3-methoxyphenylboronic acid (0.019 g, 0.123 mmol),tert-butyl2-(((1s,4s)-4-((4-bromo-5-(cyanomethoxy)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(0.064 g, 0.123 mmol), aq. Na₂CO₃ (2 M solution, 0.123 mL, 0.247 mmol),and Pd(PPh₃)₄(0.004 g, 0.004 mmol) in EtOH (1.0 mL) and benzene (3.0mL). The reaction mixture was then heated in a microwave at 130° C. for1 h, quenched with H₂O and extracted with EtOAc (2×). The combinedorganics layers were dried over MgSO₄, filtered and concentrated to givethe title compounds as a dark solid mixture without furtherpurification. LCMS m/z=546.5 [M+H]⁺.

Step E: Preparation of2-(((1s,4s)-4-((3-(2-Amino-2-oxoethoxy)-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To tert-butyl2-(((1r,4r)-4-((3-(2-Amino-2-oxoethoxy)-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-(2-Amino-2-oxoethoxy)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateobtained was added 4 M HCl (0.309 mL, 1.23 mmol) in 1,4-dioxane. Thereaction was stirred at 25° C. for 16 h, and concentrated to give ayellow oil. This yellow oil was purified by HPLC to give the titlecompound (0.004 g) as a white solid.

LCMS m/z=508.3 [M+H]⁺.

Example 1.90: Preparation of2-(((1s,4s)-4-((5-(2-Amino-2-oxoethoxy)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 278)

From the same mixture of tert-butyl2-(((1s,4s)-4-((3-(cyanomethoxy)-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-(cyanomethoxy)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateobtained, using a similar method to the one described in Example 1.89,Step E, the title compound was also isolated as a white solid. LCMSm/z=509.4 [M+H]⁺.

Example 1.91: Preparation of2-(((1r,4r)-4-((3-(2-Amino-2-oxoethoxy)-4-(2-fluoro-3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 279)

From 2-fluoro-3-methoxyphenylboronic acid and a mixture of tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-(cyanomethoxy)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-Bromo-3-(cyanomethoxy)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.89, Step D&E,the title compound was obtained as a white solid. LCMS m/z=526.8 [M+H]⁺.

Example 1.92: Preparation of2-(((1s,4s)-4-((5-(2-Amino-2-oxoethoxy)-4-(2-fluoro-3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 280)

From 2-fluoro-3-methoxyphenylboronic acid and a mixture of tert-butyl2-(((1s,4s)-4-((4-Bromo-5-(cyanomethoxy)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-Bromo-3-(cyanomethoxy)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.89, Step D&E,the title compound was obtained as a white solid. LCMS m/z=527.6 [M+H]⁺.

Example 1.93: Preparation of2-(((1s,4s)-4-((5-(Cyanomethoxy)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 283)

From 3-methoxyphenylboronic acid, using a similar method to the onedescribed in Example 1.89, Step D&E, the title compound was obtained asa white solid. LCMS m/z=490.5 [M+H]⁺.

Example 1.94: Preparation of2-(((1s,4s)-4-((4-Benzhydryl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 17)

A mixture of 4-benzhydryl-1H-pyrazole (30 mg, 0.128 mmol), tert-butyl2-(((1s,4s)-4-((methylsulfonyloxy)methyl)cyclohexyl)methoxy)acetate(43.1 mg, 0.128 mmol), potassium tert-butoxide (28.7 mg, 0.256 mmol) and18-Crown-6 (6.77 mg, 0.026 mmol) was stirred at room temperatureovernight. The mixture was purified by preparative LCMS to give thetitle compound (one of the two regioisomers separated). LCMS m/z=419.3[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.36-7.27 (m, 5H), 7.23 (m, 2H),7.17 (m, 4H), 7.03 (s, 1H), 5.34 (s, 1H), 4.07 (m, 4H), 3.46 (d, 2H,J=5.6 Hz), 2.06 (m, 1H), 1.85 (m, 1H), 1.58-1.44 (m, 6H), 1.28 (m, 2H).

Example 1.95: Preparation of2-(((1r,4r)-4-((4-Benzhydryl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 18)

A mixture of 4-benzhydryl-1H-pyrazole (30 mg, 0.128 mmol), tert-butyl2-(((1s,4s)-4-((methylsulfonyloxy)methyl)cyclohexyl)methoxy)acetate(43.1 mg, 0.128 mmol), potassium tert-butoxide (28.7 mg, 0.256 mmol) and18-Crown-6 (6.77 mg, 0.026 mmol) was stirred at room temperatureovernight. The mixture was purified by preparative LCMS to give thetitle compound (one of the two regioisomers separated). LCMS m/z=419.3[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.31-7.27 (m, 5H), 7.23 (d, 2H,J=7 Hz), 7.17 (m, 4H), 6.97 (s, 1H), 5.34 (s, 1H), 4.08 (s, 2H), 3.93(d, 2H, J=6.8 Hz), 3.36 (d, 2H, J=6.3 Hz), 1.83 (m, 3H), 1.63 (m, 3H),0.99 (m, 4H).

Example 1.96: Preparation of2-(((1s,4s)-4-((3,4-Diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 3)

A mixture of 3,4-diphenyl-1H-pyrazole (50 mg, 0.227 mmol), tert-butyl2-(((1s,4s)-4-((methylsulfonyloxy)methyl)cyclohexyl)methoxy)acetate (76mg, 0.227 mmol), potassium tert-butoxide (76 mg, 0.681 mmol) and18-Crown-6 (12.00 mg, 0.045 mmol) in DMF (2 mL) was stirred at 25° C.for 18 h. The mixture was purified by HPLC to give the title compound.LCMS m/z=405.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.47 (m, 3H), 7.30(m, 4H), 7.26 (m, 4H), 4.16 (d, 2H, J=7.6 Hz), 4.11 (s, 2H), 3.50 (d,2H, J=6.8 Hz), 2.22 (m, 1H), 1.90 (m, 1H), 1.58 (m, 6H), 1.40 (m, 2H).

Example 1.97: Preparation of2-(((1s,4s)-4-((3-Methyl-5-phenyl-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 19) Step A: Preparation of (1s,4s)-DiethylCyclohexane-1,4-dicarboxylate

To a solution of (1s,4s)-cyclohexane-1,4-dicarboxylic acid (25 g, 145mmol) in ethanol (150 mL) was added concentrated H₂SO₄ (1 mL). Thereaction was refluxed for 16 h, cooled to room temperature andconcentrated. The residue was extracted with EtOAc and saturated NaHCO₃,washed with brine, dried over MgSO₄, and filtered. The filtrate wasconcentrated to provide the title compound as a colorless oil (30.5 g).¹H NMR (400 MHz, CDCl₃) δ ppm 1.25 (t, J=7.14 Hz, 6H), 1.64-1.70 (m,4H), 1.87-1.92 (m, 4H), 2.44-2.46 (m, 2H), 4.11-1.46 (quartet, J=7.12Hz, 4H).

Step B: Preparation of (1s,4s)-cyclohexane-1,4-diyldimethanol

To a solution of (1s,4s)-diethyl cyclohexane-1,4-dicarboxylate (13.0 g,56.9 mmol) in THF (500 mL) was added lithium aluminum hydride (4.54 g,120 mmol) in portions at 0° C. The mixture was stirred at thattemperature for 2 h and quenched with cold water, filtered andconcentrated to give the title compound as colorless oil (8.2 g). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.27-1.42 (m, 8H), 1.46-1.54 (m, 2H), 3.26-3.31(m, 4H), 4.27-4.30 (t, J=5.31 Hz, 2H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-(Hydroxymethyl)cyclohexyl)methoxy)acetate

To a solution of (1s,4s)-cyclohexane-1,4-diyldimethanol (18.2 g, 126mmol) in toluene (200 mL) was added NaOH (50% aq., 60 mL) andtetrabutylammonium iodide (2.331 g, 6.31 mmol), followed bytert-butyl-2-bromoacetate (20.50 mL, 139 mmol) at room temperature. Thereaction mixture was stirred violently at room temperature for 2 h anddiluted with ethyl acetate and water.

After separation, the aqueous layer was extracted with EtOAc (3×30 mL).The combined organic layers were dried over MgSO₄, concentrated, andpurified by silica gel column chromatography to give the title compoundas colorless oil (13.5 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.35-1.47 (m,4H), 1.48 (s, 9H), 1.50-1.60 (m, 4H), 1.63-1.74 (m, 1H), 1.79-1.92 (m,1H), 3.42 (d, J=6.95 Hz, 2H), 3.55 (d, J=6.82 Hz, 2H), 3.93 (s, 1H),3.94 (s, 2H).

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-(Tosyloxymethyl)cyclohexyl)methoxy)acetate

To a solution of tert-butyl2-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methoxy)acetate (12.0 g, 46.4mmol) in dichloromethane (150 mL) were added triethylamine (4.70 g, 46.4mmol) and 4-(dimethylamino)pyridine (0.567 g, 4.64 mmol), followed by4-methylbenzene-1-sulfonyl chloride (8.86 g, 46.4 mmol). The reactionwas stirred at room temperature for 16 h. The solvent was removed andthe residue was extracted with EtOAc/H₂O. The organic extracts weredried over MgSO₄, and concentrated. The residue was purified by silicagel column chromatography to give the title compound as pale liquid (9.5g). LCMS m/z=413.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.28-1.43 (m,4H), 1.46-1.48 (m, 9H), 1.49-1.56 (m, 4H), 1.76-1.91 (m, 2H), 2.45 (s,3H), 3.36 (d, J=6.95 Hz, 2H), 3.92 (d, J=7.05 Hz, 2H), 3.92 (s, 2H),7.35 (d, J=8.46 Hz, 2H), 7.78 (d, J=8.34 Hz, 2H).

Step E: Preparation of 5-Methyl-3-phenyl-1H-pyrazole

To a solution of acetophenone (10 g, 83 mmol) in anhydrous toluene (10mL) was added LiHMDS (1.0 M in THF, 83 mL, 83 mmol) via syringe at 0° C.under argon. After 5 min, acetyl chloride (6.53 g, 83 mmol) was added inone portion via syringe. The ice bath was removed and glacial AcOH (5mL), EtOH (50 mL), and hydrazine hydrate (12.50 g, 250 mmol) were added.The mixture was refluxed for 2 h. After cooled to room temperature, thereaction was neutralized to pH 7 by adding 1.0 M NaOH solution. Themixture was extracted with EtOAc, washed with brine, dried over MgSO₄,and concentrated. The residue was purified by silica gel columnchromatography to give the title compound as pale yellow oil (12.05 g).LCMS m/z=159.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H),6.42 (s, 1H), 7.20-7.44 (m, 3H), 7.67-7.82 (m, 2H), 12.53 (bs, 1H).

Step F: Preparation of 4-Bromo-5-methyl-3-phenyl-1H-pyrazole

To a solution of 5-methyl-3-phenyl-1H-pyrazole (8.0 g, 50.6 mmol) indichloromethane (150 mL) was added bromine (8.08 g, 50.6 mmol) dropwiseat 0° C. The reaction was stirred at that temperature for 30 min andcontinued at room temperature for 2 h. After quenched with aqueoussolution of Na₂SO₃ (10% wt aq., 10 mL), the organic solvent was removedand the aqueous mixture was extracted with EtOAc, washed with brine,dried over MgSO₄, and concentrated. The residue was purified by silicagel column chromatography to give the title compound as yellow oil (9.5g).

LCMS m/z=236.9 [M+H]⁺; TH NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3H),7.30-7.57 (m, 5H), 13.12 (s, 1H).

Step G: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

To a solution of 4-bromo-5-methyl-3-phenyl-1H-pyrazole (2.0 g, 8.44mmol) in DMF (5 mL) were added sodium hydride (0.202 g, 8.44 mmol) inportions at 0° C. The reaction was stirred at that temperature for 1 hand tert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(3.48 g, 8.44 mmol) was added. The reaction was heated to 42° C.,stirred for 16 h, and quenched with H₂O (2 mL). The mixture wasextracted with ethyl acetate, dried over MgSO₄ and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound as a colorless liquid (3.05 g)(mixture of two isomers). LCMS m/z=477.3 [M+H]⁺.

Step H: Preparation of2-(((1s,4s)-4-((3-Methyl-5-phenyl-4-m-tolyl-tH-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.19 mmol) in dioxane (3 mL) wereadded m-tolylboronic acid (25.8 mg, 0.19 mmol),tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol), and K₂CO₃ (2M aq., 0.2 mL). The reaction was heated to 150° C. under microwaveirradiation for 4 h. The reaction mixture was filtered and concentrated.The residue was treated with HCl (4 M in dioxane, 5 mL) at roomtemperature for 10 h. The mixture was concentrated and purified by HPLCto give the title compound (13.5 mg) as a white solid. LCMS m/z=433.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01-1.19 (m, 4H), 1.21-1.36 (m,4H), 1.54-1.66 (m, 1H), 1.86-1.98 (m, 1H), 2.22 (s, 3H), 3.19 (d, J=6.95Hz, 2H), 3.89 (d, J=7.45 Hz, 2H), 3.91 (s, 2H), 7.04-7.11 (m, 2H),7.21-7.31 (m, 5H), 7.39-7.47 (m, 2H).

Example 1.98: Preparation of2-(((1s,4s)-4-((4-(2,5-Difluorophenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 20)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers, and 2,5-difluorophenylboronic acid, thetitle compound was obtained using a similar method to the one describedin Example 1.97. LCMS m/z=455.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.99-1.21 (m, 4H), 1.21-1.38 (m, 4H), 1.54-1.66 (m, 1H), 1.88-2.02 (m,1H), 2.13 (s, 3H), 3.20 (d, J=7.07 Hz, 2H), 3.91 (s, 2H), 3.93 (d,J=7.07 Hz, 2H), 6.93-7.00 (m, 1H), 7.05-7.27 (m, 5H), 7.38-7.43 (m, 2H).

Example 1.99: Preparation of2-(((1s,4s)-4-((4-(4-Fluorophenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 22)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 4-fluorophenylboronic, the titlecompound was obtained using a similar method to the one described inExample 1.97. LCMS m/z=437.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.33-1.54 (m, 8H), 1.71-1.82 (m, 1H), 2.05-2.15 (m, 1H), 2.20 (s, 3H),3.43 (d, J=7.07 Hz, 2H), 4.00 (s, 2H), 4.05 (d, J=7.58 Hz, 2H),7.17-7.21 (m, 3H), 7.21-7.28 (m, 3H), 7.29-7.34 (m, 3H).

Example 1.100: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 23)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound was obtained using a similar method to the one described inExample 1.97. LCMS m/z=453.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.34-1.55 (m, 8H), 1.73-1.82 (m, 1H), 2.04-2.16 (m, 1H), 2.23 (s, 3H),3.43 (d, J=7.07 Hz, 2H), 4.01 (s, 2H), 4.06 (d, J=7.58 Hz, 2H),7.09-7.14 (m, 1H), 7.18-7.41 (m, 8H).

Example 1.101: Preparation of2-(((1s,4s)-4-((5-Methyl-3-phenyl-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 24)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and m-tolylboronic acid, the title compoundwas obtained using a similar method to the one described in Example1.97. LCMS m/z=433.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.55(m, 8H), 1.72-1.82 (m, 1H), 2.07-2.15 (m, 1H), 2.19 (s, 3H), 2.28 (s,3H), 3.43 (d, J=6.82 Hz, 2H), 4.00 (s, 2H), 4.05 (d, J=7.58 Hz, 2H),6.88-7.14 (m, 3H), 7.15-7.29 (m, 3H), 7.29-7.39 (m, 3H).

Example 1.102: Preparation of2-(((1s,4s)-4-((4-(4-Fluorophenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 25)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 4-fluorophenylboronic acid, the titlecompound was obtained using a similar method to the one described inExample 1.97. LCMS m/z=437.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.01-1.20 (m, 4H), 1.21-1.36 (m, 4H), 1.52-1.67 (m, 1H), 1.86-2.00 (m,1H), 2.20 (s, 3H), 3.19 (d, J=6.82 Hz, 2H), 3.88 (d, J=7.58 Hz, 2H),3.91 (s, 2H), 6.96-7.17 (m, 4H), 7.18-7.31 (m, 2H), 7.34-7.48 (m, 3H).

Example 1.103: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 26)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2,3-difluorophenylboronic acid, thetitle compound was obtained using a similar method to the one describedin Example 1.97. LCMS m/z=455.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.98-1.20 (m, 4H), 1.21-1.38 (m, 4H), 1.53-1.69 (m, 1H), 1.88-2.02 (m,1H), 2.13 (s, 3H), 3.19 (d, J=7.07 Hz, 2H), 3.91 (s, 2H), 3.94 (d,J=7.33 Hz, 2H), 6.91-6.97 (m, 1H), 7.05-7.12 (m, 1H), 7.20-7.25 (m, 3H),7.37-7.42 (m, 3H).

Example 1.104: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 27)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2,3-difluorophenylboronic acid, thetitle compound was obtained using a similar method to the one describedin Example 1.97. LCMS m/z=455.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.31-1.54 (m, 8H), 1.71-1.81 (m, 1H), 2.05-2.15 (m, 1H), 2.17 (s, 3H),3.42 (d, J=7.07 Hz, 2H), 3.99 (s, 2H), 4.07 (d, J=7.58 Hz, 2H),7.02-7.09 (m, 2H), 7.19-7.32 (m, 4H), 7.34-7.46 (m, 2H).

Example 1.105: Preparation of2-(((1s,4s)-4-((4-(4-Chlorophenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 28)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 4-chlorophenylboronic acid, the titlecompound was obtained using a similar method to the one described inExample 1.97. LCMS m/z=453.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.31-1.57 (m, 8H), 1.70-1.83 (m, 1H), 2.03-2.14 (m, 1H), 2.21 (s, 3H),3.42 (d, J=6.95 Hz, 2H), 4.00 (s, 2H), 4.05 (d, J=7.58 Hz, 2H),7.14-7.20 (m, 2H), 7.22-7.34 (m, 5H), 7.38-7.44 (m, 2H).

Example 1.106: Preparation of2-(((1s,4s)-4-((4-(2,5-Difluorophenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 29)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2,5-difluorophenylboronic acid, thetitle compound was obtained using a similar method to the one describedin Example 1.97. LCMS m/z=455.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.99-1.21 (m, 4H), 1.21-1.38 (m, 4H), 1.54-1.66 (m, 1H), 1.88-2.02 (m,1H), 2.13 (s, 3H), 3.20 (d, J=7.07 Hz, 2H), 3.91 (s, 2H), 3.93 (d,J=7.07 Hz, 2H), 6.93-7.00 (m, 1H), 7.05-7.27 (m, 5H), 7.38-7.43 (m, 2H).

Example 1.107: Preparation of2-(((1s,4s)-4-((5-(3-Methoxyphenyl)-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 32) Step A: Preparation of3-Bromo-5-methyl-4-phenyl-1H-pyrazole

To a solution of 5-methyl-4-phenyl-1H-pyrazole (3.0 g, 18.96 mmol) inacetic acid (glacial, 100 mL) was added bromine (1.457 mL, 28.4 mmol) atroom temperature. The reaction was stirred at room temperature for 2 h.After quenched with aqueous solution of Na₂SO₃ (10% wt aq., 10 mL), thereaction was concentrated and extracted with EtOAc, washed with brine,dried over MgSO₄, and purified by silica gel column chromatography togive the title compound as yellow oil (2.8 g).

LCMS m/z=236.9 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3H),7.24-7.54 (m, 5H), 13.13 (s, 1H).

Step B: Preparation of tert-Butyl2-(((1s,4s)-4-((5-Bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((3-Bromo-5-methyl-4-phenyl-1H-pyrazol-1-y)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

A solution of 3-bromo-5-methyl-4-phenyl-1H-pyrazole (2.0 g, 7.04 mmol)in DMF (10 mL) was treated with sodium hydride (0.169 g, 7.04 mmol) at0° C. for 1 h, then a solution of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (2.90 g, 7.04mmol) in DMF (5 mL) was added. The reaction mixture was gently warmed to60° C. for 16 h and quenched by water (2 mL).

The mixture was extracted by EtOAc, dried over MgSO₄, and purified bysilica gel column chromatography to give the title compound (2.25 g)(mixture of two regioisomers). LCMS m/z=477.3 [M+H]⁺.

Step C: Preparation of2-(((1s,4s)-4-((5-(3-Methoxyphenyl)-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.19 mmol) in dioxane (3 mL) wereadded 3-methoxyphenylboronic acid (28.9 mg, 0.19 mmol),tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol), and K₂CO₃ (2M aq., 0.2 mL). The reaction was heated to 150° C. under microwaveirradiation for 4 h. The reaction mixture was filtered and concentrated.The residue was treated with HCl (4.0 M in dioxane, 5 mL) at roomtemperature for 10 h. The mixture was concentrated and purified by HPLCto give the title compound (one of the two regioisomers separated) as awhite solid. LCMS m/z=449.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.09-1.20 (m, 4H), 1.22-1.38 (m, 4H), 1.57-1.69 (m, 1H), 1.89-1.99 (m,1H), 2.21 (s, 3H), 3.23 (d, J=6.82 Hz, 2H), 3.77 (s, 3H), 3.86 (d,J=7.33 Hz, 2H), 3.92 (s, 2H), 6.94-6.99 (m, 2H), 7.04-7.10 (m, 2H),7.11-7.19 (m, 3H), 7.20-7.26 (m, 2H).

Example 1.108: Preparation of2-(((1s,4s)-4-((3-(3-Methoxyphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 33)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.107. LCMS m/z=449.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.54 (m, 8H), 1.71-1.80 (m,1H), 2.04-2.14 (m, 1H), 2.19 (s, 3H), 3.42 (d, J=6.82 Hz, 2H), 3.71 (s,3H), 3.99 (s, 2H), 4.03 (d, J=7.58 Hz, 2H), 6.77-6.84 (m, 2H), 7.12-7.19(m, 2H), 7.20-7.31 (m, 3H), 7.32-7.39 (m, 2H).

Example 1.109: Preparation of2-(((1s,4s)-4-((5-(3-Fluoro-5-methoxyphenyl)-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 34)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluoro-5-methoxyphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.107. LCMSm/z=467.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09-1.22 (m, 4H),1.23-1.39 (m, 4H), 1.56-1.69 (m, 1H), 1.88-2.00 (m, 1H), 2.20 (s, 3H),3.24 (d, J=6.32 Hz, 2H), 3.72 (s, 3H), 3.79 (d, J=7.57 Hz, 2H), 3.93 (s,2H), 6.60-6.92 (m, 3H), 7.05-7.35 (m, 5H).

Example 1.110: Preparation of2-(((1s,4s)-4-((3-(3-Fluoro-5-methoxyphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 35)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluoro-5-methoxyphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.107. LCMSm/z=467.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.54 (m, 8H),1.71-1.81 (m, 1H), 2.05-2.14 (m, 1H), 2.18 (s, 3H), 3.42 (d, J=6.82 Hz,2H), 3.59 (s, 3H), 3.99 (s, 2H), 4.05 (d, J=7.58 Hz, 2H), 6.62-6.71 (m,4H), 7.17-7.23 (m, 1H), 7.29-7.44 (m, 3H).

Example 1.111: Preparation of2-(((1s,4s)-4-((4-(4-Methoxyphenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 38)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 4-methoxyphenylboronic acid (26.6 mg,0.19 mmol), the title compound (one of the two regioisomers separated)was obtained using a similar method to the one described in Example1.97. LCMS m/z=449.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.54(m, 8H), 1.71-1.81 (m, 1H), 2.04-2.14 (m, 1H), 2.17 (s, 3H), 3.42 (d,J=6.82 Hz, 2H), 3.77 (s, 3H), 4.00 (s, 2H), 4.04 (d, J=7.58 Hz, 2H),6.90-6.96 (m, 2H), 7.04-7.11 (m, 2H), 7.16-7.27 (m, 3H), 7.30-7.37 (m,2H).

Example 1.112: Preparation of2-(((1s,4s)-4-((4-(3-Fluoro-5-methoxyphenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 39)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluoro-5-methoxyphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.97. LCMSm/z=467.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.55 (m, 8H),1.70-1.82 (m, 1H), 2.03-2.14 (m, 1H), 2.23 (s, 3H), 3.42 (d, J=7.07 Hz,2H), 3.70 (s, 3H), 3.99 (s, 2H), 4.04 (d, J=7.58 Hz, 2H), 6.39-6.81 (m,3H), 7.19-7.36 (m, 5H).

Example 1.113: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 40)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.97. LCMS m/z=437.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.53 (m, 8H), 1.72-1.81 (m,1H), 2.04-2.15 (m, 1H), 2.23 (s, 3H), 3.43 (d, J=7.07 Hz, 2H), 4.00 (s,2H), 4.06 (d, J=7.58 Hz, 2H), 6.93-7.01 (m, 2H), 7.08-7.15 (m, 1H),7.20-7.35 (m, 5H), 7.35-7.44 (m, 1H).

Example 1.114: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 41)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.97. LCMS m/z=453.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02-1.20 (m, 4H), 1.21-1.35 (m,4H), 1.54-1.65 (m, 1H), 1.88-1.98 (m, 1H), 2.24 (s, 3H), 3.20 (d, J=6.82Hz, 2H), 3.89 (d, J=7.58 Hz, 2H), 3.91 (s, 2H), 7.00-7.08 (m, 2H),7.17-7.30 (m, 5H), 7.40-7.48 (m, 2H).

Example 1.115: Preparation of2-(((1s,4s)-4-((4-(4-Methoxyphenyl)-3-methyl-5-phenyl-II-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 42)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 4-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.97. LCMS m/z=449.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01-1.19 (m, 4H), 1.20-1.35 (m,4H), 1.54-1.64 (m, 1H), 1.86-1.97 (m, 11-), 2.19 (s, 3H), 3.19 (d,J=6.82 Hz, 2H), 3.69 (s, 3H), 3.87 (d, J=7.33 Hz, 2H), 3.91 (s, 2H),6.76-6.82 (m, 2H), 6.95-7.02 (m, 2H), 7.19-7.26 (m, 2H), 7.35-7.45 (m,3H).

Example 1.116: Preparation of2-(((1s,4s)-4-((4-(3-Fluoro-5-methoxyphenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 43)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluoro-5-methoxyphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.97. LCMSm/z=467.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01-1.20 (m, 4H),1.21-1.36 (m, 4H), 1.56-1.64 (m, 1H), 1.88-1.97 (m, 1H), 2.25 (s, 3H),3.20 (d, J=7.07 Hz, 2H), 3.60 (s, 3H), 3.87 (d, J=7.33 Hz, 2H), 3.91 (s,2H), 6.36-6.65 (m, 4H), 7.20-7.52 (m, 4H).

Example 1.117: Preparation of2-(((1s,4s)-4-((4-(2-Chlorophenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 44)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.97. LCMS m/z=453.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.53 (m, 8H), 1.71-1.82 (m,1H), 2.08 (s, 3H), 2.08-2.17 (m, 1H), 3.42 (d, J=6.82 Hz, 2H), 3.99 (s,2H), 4.06 (d, J=7.58 Hz, 2H), 7.16-7.30 (m, 4H), 7.33-7.44 (m, 3H),7.52-7.59 (m, 2H).

Example 1.118: Preparation of2-(((1s,4s)-4-((4-(2-Chlorophenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 45)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.97. LCMS m/z=453.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.20 (m, 4H), 1.20-1.37 (m,4H), 1.55-1.64 (m, 1H), 1.91-2.00 (m, 1H), 2.03 (s, 3H), 3.18 (d, J=6.82Hz, 2H), 3.90 (s, 2H), 3.95 (d, J=7.58 Hz, 2H), 7.14-7.29 (m, 4H),7.31-7.39 (m, 3H), 7.41-7.45 (m, 2H).

Example 1.119: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 46)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.97. LCMS m/z=437.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02-1.19 (m, 4H), 1.21-1.36 (m,4H), 1.55-1.66 (m, 1H), 1.87-1.98 (m, 1H), 2.24 (s, 3H), 3.20 (d, J=7.07Hz, 2H), 3.88 (d, J=7.33 Hz, 2H), 3.91 (s, 2H), 6.79-7.01 (m, 3H),7.22-7.30 (m, 3H), 7.40-7.47 (m, 3H).

Example 1.120: Preparation of2-(((1s,4s)-4-((5-Methyl-3-phenyl-4-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 47)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers andp-tolylboronic acid, the title compound(one of the two regioisomers separated) was obtained using a similarmethod to the one described in Example 1.97. LCMS m/z=433.2 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.53 (m, 8H), 1.71-1.80 (m, 1H),2.04-2.14 (m, 1H), 2.18 (s, 3H), 2.32 (s, 3H), 3.42 (d, J=7.07 Hz, 2H),3.99 (s, 2H), 4.04 (d, J=7.58 Hz, 2H), 7.02-7.07 (m, 2H), 7.14-7.27 (m,5H), 7.30-7.35 (m, 2H).

Example 1.121: Preparation of2-(((1s,4s)-4-((4-(2,4-Difluorophenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 48)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2,4-difluorophenylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.97. LCMSm/z=455.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.53 (m, 8H),1.72-1.81 (m, 1H), 2.06-2.13 (m, 1H), 2.14 (s, 3H), 3.43 (d, J=7.07 Hz,2H), 4.00 (s, 2H), 4.07 (d, J=7.58 Hz, 2H), 7.07-7.15 (m, 2H), 7.19-7.34(m, 6H).

Example 1.122: Preparation of2-(((1s,4s)-4-((4-(4-Chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 49) Step A: Preparation of 4-Bromo-3-phenyl-1H-pyrazole

To a solution of 3-phenyl-1H-pyrazole-4-carbaldehyde (10.0 g, 58.1 mmol)in acetic acid (100 mL, 58.1 mmol) was added bromine (10 mL, 195 mmol)dropwise at room temperature. The reaction was stirred at roomtemperature for 2 h. After quenched with aqueous solution of Na₂SO₃ (10%wt aq., 10 mL), the reaction was concentrated and extracted with EtOAc,washed with brine, dried over MgSO₄, and purified by silica gel columnchromatography to give the title compound as yellow oil (10.2 g). LCMSm/z=223.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.37-7.53 (m, 3H),7.76-7.84 (m, 2H), 7.91 (s, 1H).

Step B: Preparation of tert-Butyl2-((1s,4s)-4-((4-Bromo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

A solution of 3-bromo-5-methyl-4-phenyl-1H-pyrazole (2.0 g, 7.04 mmol)in DMF (10 mL) was treated with sodium hydride (0.169 g, 7.04 mmol) at0° C. for 1 h, then a solution of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (2.90 g, 7.04mmol) in DMF (5 mL) was added. The reaction mixture was gently warmed to60° C. for 16 h and quenched by water (2 mL).

The mixture was extracted by EtOAc, dried over MgSO₄, and concentrated.The residue was purified by column chromatography to give the titlecompound as a mixture of regioisomers (2.25 g). LCMS m/z=462.2 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22-1.33 (m, 4H), 1.35-1.48 (m, 4H),1.43 (s, 9H), 1.65-1.79 (m, 1H), 2.02-2.15 (m, ill), 3.37 (d, J=6.82 Hz,2H), 3.95 (s, 2H), 4.09 (d, J=7.58 Hz, 2H), 7.34-7.51 (m, 3H), 7.76-7.84(m, 2H), 8.08 (s, 1H).

Step C: Preparation of2-(((1s,4s)-4-((4-(4-Chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.22 mmol) in dioxane (3 mL) wereadded 4-chlorophenylboronic acid (34.4 mg, 0.22 mmol),tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmol), and K₂CO₃ (2M aq., 0.2 mL). The reaction was heated to 150° C. under microwaveirradiation for 4 h. The reaction mixture was filtered and concentrated.The residue was treated with HCl (4.0 M in dioxane, 5 mL) at roomtemperature for 10 h. The mixture was concentrated and purified by HPLCto give the title compound (one of the two regioisomers separated) as awhite solid. LCMS m/z=438.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.29-1.52 (m, 8H), 1.71-1.79 (m, 1H), 2.07-2.19 (m, 1H), 3.40 (d, J=6.82Hz, 2H), 3.99 (s, 2H), 4.09 (d, J=7.83 Hz, 2H), 7.21-7.27 (m, 2H),7.29-7.42 (m, 7H), 7.98 (s, 1H).

Example 1.123: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 50)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.122. LCMS m/z=423.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27-1.55 (m, 8H), 1.67-1.84 (m,1H), 2.07-2.22 (m, 1H), 3.41 (d, J=6.82 Hz, 2H), 4.00 (s, 2H), 4.10 (d,J=7.58 Hz, 2H), 6.99-7.10 (m, 3H), 7.29-7.43 (m, 6H), 8.04 (s, 1H).

Example 1.124: Preparation of2-(((1s,4s)-4-((4-(4-Fluorophenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 51)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 4-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.122. LCMS m/z=423.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28-1.53 (m, 8H), 1.70-1.80 (m,1H), 2.08-2.18 (m, 1H), 3.40 (d, J=6.82 Hz, 2H), 3.99 (s, 2H), 4.09 (d,J=7.58 Hz, 2H), 7.10-7.17 (m, 2H), 7.22-7.36 (m, 5H), 7.36-7.41 (m, 2H),7.93 (s, 1H).

Example 1.125: Preparation of2-((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 52)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chloro-2-fluorophenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.97. LCMSm/z=470.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.54 (m, 8H),1.71-1.82 (m, 1H), 2.05-2.14 (m, 1H), 2.16 (s, 3H), 3.43 (d, J=7.07 Hz,2H), 4.00 (s, 2H), 4.07 (d, J=7.58 Hz, 2H), 7.16-7.36 (m, 6H), 7.50-7.63(m, 2H).

Example 1.126: Preparation of2-(((1s,4s)-4-((4-(2,4-Difluorophenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 53)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2,4-difluorophenylboronic acid, thetitle compound was obtained using a similar method to the one describedin Example 1.97. LCMS m/z=455.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) & ppm1.02-1.18 (m, 4H), 1.21-1.35 (m, 4H), 1.55-1.64 (m, 1H), 1.89-1.99 (m,1H), 2.10 (s, 3H), 3.19 (d, J=7.07 Hz, 2H), 3.91 (s, 2H), 3.93 (d,J=7.33 Hz, 2H), 6.94-7.02 (m, 2H), 7.11-7.24 (m, 3H), 7.34-7.43 (m, 3H).

Example 1.127: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 54)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chloro-2-fluorophenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.97. LCMSm/z=470.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) & ppm 1.01-1.20 (m, 4H),1.21-1.39 (m, 4H), 1.54-1.66 (m, 1H), 1.90-2.00 (m, 1H), 2.12 (s, 3H),3.20 (d, J=6.82 Hz, 2H), 3.91 (s, 2H), 3.94 (d, J=7.58 Hz, 2H),7.05-7.30 (m, 4H), 7.34-7.53 (m, 4H).

Example 1.128: Preparation of2-(((1s,4s)-4-((3-Methyl-5-phenyl-4-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 55)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and p-tolylboronic acid, the title compound(one of the two regioisomers separated) was obtained using a similarmethod to the one described in Example 1.97. LCMS m/z=433.2 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.25-1.50 (m, 8H), 1.68-1.79 (m, 1H),1.98-2.08 (m, 1H), 2.07 (s, 3H), 2.31 (s, 3H), 3.40 (d, J=7.07 Hz, 2H),3.98 (s, 2H), 4.06 (d, J=7.58 Hz, 2H), 7.33-7.39 (m, 2H), 7.40-7.47 (m,4H), 7.77-7.82 (m, 3H).

Example 1.129: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-4-fluorophenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 56)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chloro-4-fluorophenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.97. LCMSm/z=471.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02-1.18 (m, 4H),1.21-1.36 (m, 4H), 1.55-1.65 (m, 1H), 1.87-1.98 (m, 1H), 2.23 (s, 3H),3.20 (d, J=6.82 Hz, 2H), 3.89 (d, J=7.58 Hz, 2H), 3.91 (s, 2H),7.01-7.08 (m, 1H), 7.18-7.29 (m, 4H), 7.41-7.48 (m, 3H).

Example 1.130: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-4-fluorophenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 57)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chloro-4-fluorophenylboronic acid,the title compound was obtained using a similar method to the onedescribed in Example 1.97. LCMS m/z=471.1 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) ppm 1.33-1.55 (m, 8H), 1.72-1.83 (m, 1H), 2.05-2.15 (m, 1H),2.22 (s, 3H), 3.44 (d, J=7.07 Hz, 2H), 4.01 (s, 2H), 4.06 (d, J=7.58 Hz,2H), 7.10-7.17 (m, 1H), 7.21-7.42 (m, 7H).

Example 1.131: Preparation of2-(((1s,4s)-4-((4-(4-Methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 58)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.22 mmol) and4-methoxyphenylboronic acid, the title compound (one of the tworegioisomers separated) was obtained using a similar method to the onedescribed in Example 1.122. LCMS m/z=435.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.26-1.54 (m, 8H), 1.65-1.81 (m, 1H), 2.03-2.19 (m, 1H),3.40 (d, J=6.82 Hz, 2H), 3.75 (s, 3H), 3.99 (s, 2H), 4.07 (d, J=7.58 Hz,2H), 6.85-6.92 (m, 2H), 7.11-7.18 (m, 2H), 7.23-7.34 (m, 3H), 7.37-7.43(m, 2H), 7.84 (s, 1H).

Example 1.132: Preparation of2-(((1s,4s)-4-((4-(2-Methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 59)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.122. LCMS m/z=435.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29-1.52 (m, 8H), 1.69-1.80 (m,1H), 2.13 (dd, J=6.57, 3.79 Hz, 1H), 3.40 (d, J=6.82 Hz, 2H), 3.52 (s,3H), 3.99 (s, 2H), 4.09 (d, J=7.58 Hz, 2H), 6.85-6.93 (m, 2H), 7.08-7.13(m, 2H), 7.18-7.31 (m, 3H), 7.32-7.38 (m, 2H), 7.77 (s, 1H).

Example 1.133: Preparation of2-(((1s,4s)-4-((3-Phenyl-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 60)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and m-tolylboronic acid, the title compound(one of the two regioisomers separated) was obtained using a similarmethod to the one described in Example 1.122. LCMS m/z=419.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.29-1.53 (m, 8H), 1.70-1.81 (m, 1H),2.07-2.18 (m, 1H), 2.25 (s, 3H), 3.40 (d, J=7.07 Hz, 2H), 3.99 (s, 2H),4.09 (d, J=7.58 Hz, 2H), 6.96-7.08 (m, 2H), 7.09-7.21 (m, 2H), 7.25-7.35(m, 3H), 7.38-7.44 (m, 2H), 7.90 (s, 1H).

Example 1.134: Preparation of2-(((1s,4s)-4-((3-Phenyl-4-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 61)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and p-tolylboronic acid, the title compound(one of the two regioisomers separated) was obtained using a similarmethod to the one described in Example 1.122. LCMS m/z=419.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.28-1.51 (m, 8H), 1.70-1.80 (m, 1H),2.08-2.18 (m, 1H), 2.29 (s, 3H), 3.40 (d, J=7.07 Hz, 2H), 3.99 (s, 2H),4.08 (d, J=7.58 Hz, 2H), 7.10-7.16 (m, 3H), 7.26-7.36 (m, 3H), 7.37-7.44(m, 3H), 7.88 (s, 1H).

Example 1.135: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 62)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.122. LCMS m/z=439.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29-1.53 (m, 8H), 1.70-1.79 (m,1H), 2.08-2.19 (m, 1H), 3.40 (d, J=7.07 Hz, 2H), 4.00 (s, 2H), 4.10 (d,J=7.58 Hz, 2H), 7.15-7.19 (m, 1H), 7.25-7.42 (m, 8H), 8.05 (s, 1H).

Example 1.136: Preparation of2-(((1s,4s)-4-((4-(2-Fluorophenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 63)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.122. LCMS m/z=423.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29-1.53 (m, 8H), 1.71-1.81 (m,1H), 2.09-2.20 (m, 1H), 3.41 (d, J=7.07 Hz, 2H), 4.00 (s, 2H), 4.12 (d,J=7.83 Hz, 2H), 7.13-7.40 (m, 9H), 7.92 (s, 1H).

Example 1.137: Preparation of2-(((1s,4s)-4-((3-Methyl-4-phenyl-5-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 64)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and m-tolylboronic acid, the title compound(one of the two regioisomers separated) was obtained using a similarmethod to the one described in Example 1.107. LCMS m/z=433.2 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ ppm 1.29-1.44 (m, 4H), 1.48 (s, 9H), 1.49-1.60(m, 4H), 1.81-1.91 (m, 1H), 2.04 (s, 3H), 2.12-2.20 (m, 1H), 3.25 (d,J=6.95 Hz, 2H), 3.87 (s, 2H), 4.02 (d, J=7.58 Hz, 2H), 7.30-7.37 (m,1H), 7.37-7.49 (m, 3H), 7.84-7.89 (m, 1H).

Example 1.138: Preparation of2-(((1s,4s)-4-((5-Methyl-4-phenyl-3-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 65)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and m-tolylboronic acid, the title compoundwas obtained using a similar method to the one described in Example1.107. LCMS m/z=433.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26-1.50(m, 8H), 1.43 (s, 9H), 1.66-1.78 (m, 1H), 1.97-2.09 (m, 1H), 2.30 (s,3H), 3.39 (d, J=6.82 Hz, 2H), 3.94 (s, 2H), 4.06 (d, J=7.58 Hz, 2H),7.30-7.50 (m, 3H), 7.74-7.85 (m, 2H).

Example 1.139: Preparation of2-(((1s,4s)-4-((3-(3-Chlorophenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 66)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.107. LCMS m/z=453.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.54 (m, 8H), 1.73-1.81 (m,1H), 2.06-2.15 (m, 1H), 2.20 (s, 3H), 3.43 (d, J=6.82 Hz, 2H), 4.00 (s,2H), 4.06 (d, J=7.58 Hz, 2H), 7.16-7.29 (m, 5H), 7.31-7.43 (m, 4H).

Example 1.140: Preparation of2-(((1s,4s)-4-((5-(3-Fluorophenyl)-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 67)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.107. LCMS m/z=437.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.20 (m, 4H), 1.22-1.37 (m,4H), 1.56-1.64 (m, 1H), 1.86-1.96 (m, 1H), 2.21 (s, 3H), 3.22 (d, J=6.82Hz, 2H), 3.91 (d, J=7.53 Hz, 2H), 3.91 (s, 2H), 7.04-7.29 (m, 7H),7.41-7.50 (m, 2H).

Example 1.141: Preparation of2-(((1s,4s)-4-((3-(3-Fluorophenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 68)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.107. LCMS m/z=437.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.54 (m, 8H), 1.71-1.81 (m,1H), 2.05-2.15 (m, 1H), 2.19 (s, 3H), 3.42 (d, J=7.07 Hz, 2H), 4.00 (s,2H), 4.06 (d, J=7.58 Hz, 2H), 6.99-7.08 (m, 2H), 7.12-7.21 (m, 3H),7.23-7.44 (m, 4H).

Example 1.142: Preparation of2-(((1s,4s)-4-((5-(3-Chloro-2-fluorophenyl)-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 69)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chloro-2-fluorophenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.107. LCMSm/z=470.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.21 (m, 4H),1.22-1.37 (m, 4H), 1.55-1.72 (m, 1H), 1.89-2.00 (m, 1H), 2.24 (s, 3H),3.21 (d, J=6.82 Hz, 2H), 3.67 (d, J=7.58 Hz, 2H), 3.91 (s, 2H),7.03-7.11 (m, 2H), 7.14-7.39 (m, 6H).

Example 1.143: Preparation of2-(((1s,4s)-4-((3-(3-Chloro-2-fluorophenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 70)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chloro-2-fluorophenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.107. LCMSm/z=470.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.54 (m, 8H),1.70-1.81 (m, 1H), 2.04-2.14 (m, 1H), 2.30 (s, 3H), 3.42 (d, J=6.82 Hz,2H), 3.99 (s, 2H), 4.08 (d, J=7.58 Hz, 2H), 7.05-7.11 (m, 2H), 7.16-7.34(m, 4H), 7.48-7.56 (m, 2H).

Example 1.144: Preparation of2-(((1s,4s)-4-((5-(2-Fluorophenyl)-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 71)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.107. LCMS m/z=437.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02-1.19 (m, 4H), 1.22-1.35 (m,4H), 1.88-1.98 (m, 1H), 2.05-2.14 (m, 1H), 2.24 (s, 3H), 3.42 (d, J=7.07Hz, 2H), 3.99 (s, 2H), 4.07 (d, J=7.58 Hz, 2H), 7.03-7.10 (m, 2H),7.12-7.39 (m, 6H), 7.43-7.54 (m, 1H).

Example 1.145: Preparation of2-(((1s,4s)-4-((3-(2-Fluorophenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 72)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.107. LCMS m/z=437.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35-1.53 (m, 8H), 1.72-1.80 (m,1H), 2.04-2.14 (m, 1H), 2.30 (s, 3H), 3.41 (d, J=7.07 Hz, 2H), 3.99 (s,2H), 4.07 (d, J=7.58 Hz, 2H), 7.03-7.10 (m, 3H), 7.12-7.38 (m, 6H).

Example 1.146: Preparation of2-(((1s,4s)-4-((5-(2,3-Difluorophenyl)-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 73)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2,3-difluorophenylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.107. LCMSm/z=455.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.22 (m, 4H),1.24-1.38 (m, 4H), 1.58-1.70 (m, 1H), 1.88-1.98 (m, 1H), 2.24 (s, 3H),3.23 (d, J=6.82 Hz, 2H), 3.92 (s, 2H), 3.98 (d, J=7.58 Hz, 2H),7.05-7.39 (m, 8H).

Example 1.147: Preparation of2-(((1s,4s)-4-((3-(2,3-Difluorophenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 74)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2,3-difluorophenylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.107. LCMSm/z=455.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.53 (m, 8H),1.72-1.81 (m, 1H), 2.04-2.14 (m, 1H), 2.29 (s, 3H), 3.42 (d, J=6.82 Hz,2H), 3.99 (s, 2H), 4.08 (d, J=7.58 Hz, 2H), 7.01-7.35 (m, 8H).

Example 1.148: Preparation of2-(((1s,4s)-4-((5-Ethoxy-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 81)

To a solution of tert-butyl2-(((1s,4s)-4-((5-ethoxy-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(100 mg, 0.20 mmol) in dioxane (4 mL) were added phenylboronic acid(24.0 mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium (22.8 mg,0.20 mmol), and K₂CO₃ (2 M aq., 0.2 mL). The reaction mixture was heatedto 150° C. under microwave for 4 h. The reaction mixture was filteredand concentrated. The residue was treated with HCl (4 M in dioxane, 5mL) at room temperature for 16 h. The mixture was concentrated andpurified by HPLC to give the title compound (one of the two regioisomersseparated) as a white solid. LCMS m/z=449.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.15-1.42 (m, 8H), 1.35 (t, J=7.35 Hz, 3H), 1.66-1.75 (m,1H), 1.87-1.95 (m, 1H), 3.02 (q, J=7.35 Hz, 2H), 3.35 (d, J=6.82 Hz,2H), 3.99 (s, 2H), 4.08 (d, J=7.58 Hz, 2H), 7.08-7.32 (m, 8H), 7.40-7.48(m, 2H).

Example 1.149: Preparation of2-(((1s,4s)-4-((5-(Ethylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 88)

To a solution of tert-butyl2-(((1s,4s)-4-((5-(ethylthio)-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-(ethylthio)-4-iodo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.18 mmol) in dioxane (4 mL) wereadded phenylboronic acid (21.9 mg, 0.18 mmol),tetrakis(triphenylphosphine)palladium (22.8 mg, 0.20 mmol), and K₂CO₃ (2M aq., 0.2 mL). The reaction mixture was heated to 150° C. undermicrowave for 4 h. The reaction mixture was filtered and concentrated.The residue was treated with HCl (4 M in dioxane, 5 mL) at roomtemperature for 16 h. The mixture was concentrated and purified by HPLCto give the title compound (one of the two regioisomers separated) aswhite solid. LCMS m/z=465.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.05-1.36 (m, 8H), 1.24 (t, J=7.33 Hz, 3H), 1.56-1.65 (m, 1H), 1.87-1.99(m, 1H), 2.92 (q, J=7.33 Hz, 2H), 3.20 (d, J=6.82 Hz, 2H), 3.91 (s, 2H),3.94 (d, J=7.58 Hz, 2H), 7.07-7.31 (m, 8H), 7.38-7.45 (m, 2H).

Example 1.150: Preparation of2-(((1s,4s)-4-((5-(Ethylthio)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 89)

From tert-butyl2-(((1s,4s)-4-((5-(ethylthio)-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-(ethylthio)-4-iodo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.149. LCMS m/z=495.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.96 (t, J=7.33 Hz, 3H),1.32-1.55 (m, 8H), 1.70-1.81 (m, 1H), 2.15-2.25 (m, 1H), 2.53 (q, J=7.58Hz, 2H), 3.42 (d, J=7.07 Hz, 2H), 3.70 (s, 3H), 4.00 (s, 2H), 4.28 (d,J=7.58 Hz, 2H), 6.79-6.95 (m, 4H), 7.21-7.32 (m, 3H), 7.33-7.40 (m, 2H).

Example 1.151: Preparation of2-(((1s,4s)-4-((4-(3-Fluoro-5-methoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 93)

To a solution of tert-butyl2-(((1s,4s)-4-((4-iodo-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-3-(methylthio)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.18 mmol) in dioxane (3 mL) wereadded 3-fluoro-5-methoxyphenylboronic acid (30.6 mg, 0.18 mmol),tetrakis(triphenylphosphine)palladium (20.8 mg, 0.20 mmol), and K₂CO₃ (2M aq., 0.2 mL). The reaction mixture was heated to 150° C. undermicrowave for 4 h. The reaction mixture was filtered and concentrated.The residue was treated with HCl (4 M in dioxane, 5 mL) at roomtemperature for 16 h. The mixture was concentrated and purified by HPLCto give the title compound (one of the two regioisomers separated) as awhite solid. LCMS m/z=499.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.31-1.56 (m, 8H), 1.62-1.82 (m, 1H), 2.12-2.24 (m, 1H), 2.17 (s, 3H),3.35 (d, J=6.95 Hz, 2H), 3.54 (s, 2H), 3.72 (s, 3H), 4.27 (d, J=7.58 Hz,2H), 6.60-6.70 (m, 2H), 6.75-6.87 (m, 2H), 7.19-7.41 (m, 4H).

Example 1.152: Preparation of2-(((1s,4s)-4-((3-Ethyl-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 98) Step A: Preparation of 5-Ethyl-3-phenyl-1H-pyrazole

To a solution of acetophenone (10 g, 83 mmol) in anhydrous toluene (10mL) was added LiHMDS (85.0 mL, 1.0 M in THF, 85.0 mmol) via syringe at0° C. under argon. After 5 min, propionyl chloride (7.70 g, 83 mmol) wasadded in one portion via syringe. The ice bath was removed after 10 minand AcOH (2 mL), EtOH (50 mL), and hydrazine hydrate (8.35 g, 116 mmol)was added. The mixture was refluxed for 2 h. The resulting solution wasadded to 1.0 M NaOH solution, extracted with EtOAc, washed with brine,dried over MgSO₄, and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a clearyellowish liquid (12.05 g). LCMS m/z=173.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.23 (t, J=7.58 Hz, 3H), 2.64 (q, J=7.07 Hz, 2H), 6.46(s, 1H), 7.20-7.52 (m, 3H), 7.77 (d, J=6.32 Hz, 2H), 12.55 (s, 1H).

Step B: Preparation of 4-Bromo-5-ethyl-3-phenyl-1H-pyrazole

To a solution of 5-ethyl-3-phenyl-1H-pyrazole (10.0 g, 58.1 mmol) in DCM(150 mL) was added dropwise bromine (9.28 g, 58.1 mmol) at 0° C. Thereaction was stirred at that temperature for 30 min and continued for 2h at room temperature before quenched with aqueous Na₂SO₃ solution (10%wt, 10 mL). DCM was removed and the residue was extracted with EtOAc,washed with brine, dried over MgSO₄, and concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a yellow liquid (9.5 g). LCMS m/z=250.9 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.22 (t, J=7.58 Hz, 3H), 2.66 (q, J=7.58 Hz, 2H),7.40-7.56 (m, 3H), 7.82 (d, J=7.58 Hz, 2H), 13.15 (s, 1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

To a solution of 4-bromo-5-ethyl-3-phenyl-1H-pyrazole (3.0 g, 11.95mmol) in DMF (5 mL) was added sodium hydride (0.287 g, 11.95 mmol)followed by tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (4.93 g, 11.95mmol). The reaction was heated at 45° C. overnight. After quenched withwater (2 mL), the mixture was extracted with EtOAc, washed with brine,dried over MgSO₄, and concentrated. The residue was purified by silicagel column chromatography to give the title compound (a mixture ofregioisomers) as a clear liquid (4.5 g).

LCMS m/z=491.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.25 (t, J=7.20 Hz,3H), 1.31-1.43 (m, 4H), 1.49 (s, 9H), 1.51-1.60 (m, 4H), 1.76-1.90 (m,1H), 2.12-2.24 (m, 1H), 2.72 (q, J=7.75 Hz, 2H), 3.46 (d, J=6.82 Hz,2H), 3.92 (s, 2H), 4.01 (d, J=7.58 Hz, 2H), 7.31-7.43 (m, 3H), 7.86 (d,J=7.33 Hz, 2H).

Step D: Preparation of2-(((1s,4s)-4-((3-Ethyl-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.20 mmol) were added3-methoxyphenylboronic acid (30.2 mg, 0.20 mmol),tetrakis(triphenylphosphine)palladium (23.1 mg, 0.20 mmol), K₂CO₃ (2 Maq., 0.5 mL) and dioxane (3 mL) was heated to 150° C. under microwavefor 4 h. The reaction mixture was filtered and concentrated. The residuewas treated with HCl (4 M in dioxane, 5 mL) at room temperature for 10h. The mixture was concentrated and purified by HPLC to give the titlecompound (one of the two regioisomers separated) as a white solid (13.5mg). LCMS m/z=463.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01-1.18(m, 4H), 1.12 (t, J=7.58 Hz, 3H), 1.22-1.35 (m, 4H), 1.54-1.68 (m, 1H),1.87-1.98 (m, 1H), 2.63 (q, J=7.58 Hz, 2H), 3.20 (d, J=6.82 Hz, 2H),3.58 (s, 3H), 3.90 (d, J=7.32 Hz, 2H), 3.91 (s, 2H), 6.55-6.74 (m, 3H),7.10-7.17 (m, 2H), 7.22-7.28 (m, 2H), 7.36-7.44 (m, 2H).

Example 1.153: Preparation of2-(((1s,4s)-4-((3-Ethyl-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 100)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and phenylboronic acid, the title compound(one of the two regioisomers separated) was obtained using a similarmethod to the one described in Example 1.152. LCMS m/z=433.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.01-1.16 (m, 4H), 1.11 (t, J=7.58 Hz, 3H),1.22-1.34 (m, 4H), 1.55-1.66 (m, 1H), 1.83-1.96 (m, 1H), 2.60 (q, J=7.83Hz, 2H), 3.20 (d, J=6.82 Hz, 2H), 3.90 (s, 2H), 3.94 (d, J=7.33 Hz, 2H),7.04-7.26 (m, 5H), 7.35-7.57 (m, 5H).

Example 1.154: Preparation of2-(((1s,4s)-4-((5-Ethyl-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 101)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and phenylboronic acid, the title compoundwas obtained using a similar method to the one described in Example1.152. LCMS m/z=433.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (t,J=7.58 Hz, 3H), 1.30-1.57 (m, 8H), 1.72-1.83 (m, 1H), 2.08-2.18 (m, 1H),2.59 (q, J=7.49 Hz, 2H), 3.44 (d, J=7.07 Hz, 2H), 4.00 (s, 2H), 4.03 (d,J=7.33 Hz, 2H), 7.15-7.25 (m, 4H), 7.28-7.47 (m, 6H).

Example 1.155: Preparation of2-(((1s,4s)-4-((3-Ethyl-4-(3-fluorophenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 102)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.152. LCMS m/z=451.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.19 (m, 4H), 1.12 (t,J=7.45 Hz, 3H), 1.21-1.35 (m, 4H), 1.53-1.64 (m, 1H), 1.88-1.98 (m, 1H),2.64 (q, J=7.58 Hz, 2H), 3.20 (d, J=7.07 Hz, 2H), 3.91 (d, J=7.33 Hz,2H), 3.91 (s, 2H), 6.80-7.02 (m, 3H), 7.22-7.46 (m, 6H).

Example 1.156: Preparation of2-(((1s,4s)-4-((5-Ethyl-4-(3-fluorophenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 103)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.152. LCMS m/z=451.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (t, J=7.58 Hz, 3H),1.34-1.56 (m, 8H), 1.74-1.82 (m, 1H), 2.09-2.18 (m, 1H), 2.63 (q, J=7.58Hz, 2H), 3.44 (d, J=7.07 Hz, 2H), 4.00 (s, 2H), 4.04 (d, J=7.33 Hz, 2H),6.95-7.04 (m, 2H), 7.10-7.18 (m, 1H), 7.18-7.33 (m, 5H), 7.37-7.45 (m,1H).

Example 1.157: Preparation of2-(((1s,4s)-4-((3-Ethyl-4-(2-fluoro-3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 104)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluoro-3-methoxyphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.152. LCMSm/z=481.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (t, J=7.58 Hz,3H), 1.06-1.19 (m, 4H), 1.26-1.39 (m, 4H), 1.54-1.63 (m, 1H), 1.88-1.98(m, 1H), 2.64 (q, J=7.41 Hz, 2H), 3.19 (d, J=6.82 Hz, 2H), 3.77 (s, 3H),3.96 (d, J=7.58 Hz, 2H), 3.99 (s, 2H), 6.95-7.04 (m, 2H), 7.18-7.29 (m,3H), 7.32-7.42 (m, 3H).

Example 1.158: Preparation of2-(((1s,4s)-4-((5-Ethyl-4-(2-fluoro-3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 105)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluoro-3-methoxyphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.152. LCMSm/z=481.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.24 (t, J=7.58 Hz, 3H),1.32-1.70 (m, 8H), 1.85-1.99 (m, 1H), 2.15-2.27 (m, 1H), 2.65 (q, J=7.45Hz, 2H), 3.53 (d, J=7.07 Hz, 2H), 3.87 (s, 3H), 4.07 (s, 2H), 4.10 (d,J=7.71 Hz, 2H), 6.68-6.74 (m, 1H), 7.04-7.10 (m, 1H), 7.18-7.24 (m, 2H),7.29-7.38 (m, 2H), 7.45-7.55 (m, 2H).

Example 1.159: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 106)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2,3-difluorophenylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.152. LCMSm/z=469.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00 (t, J=7.45 Hz,3H), 1.03-1.13 (m, 4H), 1.22-1.32 (m, 4H), 1.54-1.65 (m, 1H), 1.81-1.90(m, 1H), 2.58 (q, J=7.58 Hz, 2H), 3.18 (d, J=6.82 Hz, 2H), 3.90 (s, 2H),3.95 (d, J=7.83 Hz, 2H), 7.07-7.14 (m, 1H), 7.19-7.32 (m, 3H), 7.36-7.58(m, 4H).

Example 1.160: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 107)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2,3-difluorophenylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.152. LCMSm/z=469.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.08 (t, J=7.58 Hz, 3H),1.38-1.68 (m, 8H), 1.85-1.95 (m, 1H), 2.17-2.27 (m, 1H), 2.66 (q, J=7.58Hz, 2H), 3.53 (d, J=7.07 Hz, 2H), 4.08 (s, 2H), 4.12 (d, J=7.58 Hz, 2H),6.96-7.02 (m, 1H), 7.11-7.18 (m, 1H), 7.20-7.26 (m, 3H), 7.28-7.33 (m,3H).

Example 1.161: Preparation of2-(((1s,4s)-4-((3-Isopropyl-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 112) Step A: Preparation of5-Isopropyl-3-phenyl-1H-pyrazole (15)

To a solution of acetophenone (1.21 g, 10.07 mmol) in dry toluene (5 mL)was added LiHMDS (11.0 mL, 1.0 M in THF, 11.0 mmol) via syringe at 0° C.under argon. After 5 min, isobutyryl chloride (1.073 g, 10.07 mmol) wasadded in one portion via syringe. The ice bath was removed and AcOH (2mL), EtOH (50 mL) and THF (5 mL) were added to form a homogeneousmixture. Hydrazine hydrate (2 mL, 10.07 mmol) was added and the reactionwas refluxed for 2 h. After cooled to room temperature, the reaction wasconcentrated and extracted with EtOAc, washed with brine, dried overMgSO₄, and concentrated. The residue was purified by silica gel columnchromatography to give the title compound as colorless oil (0.70 g).LCMS m/z=187.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.33 (d, J=6.82 Hz,6H), 2.94-3.13 (m, 1H), 6.38 (s, 1H), 7.17-7.45 (m, 5H), 10.14 (bs, 1H).

Step B: Preparation of 4-Iodo-5-isopropyl-3-phenyl-1H-pyrazole

To a solution of 5-isopropyl-3-phenyl-1H-pyrazole (0.64 g, 3.44 mmol) inTHF (20 mL) and water (20.00 mL) were added sodium iodide (0.515 g, 3.44mmol), iodine (1.308 g, 5.15 mmol), and potassium carbonate (0.712 g,5.15 mmol) at room temperature. The reaction was refluxed for 2 h,cooled to room temperature and quenched with 10% aq. Na₂SO₃. The organicsolvent was removed under reduced pressure and the aqueous residue wasextracted with EtOAc. The organic extract was washed with NaHCO₃solution, brine, dried over MgSO₄, and concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a clear liquid (0.42 g).

LCMS m/z=313.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.17 (d, J=7.07 Hz,6H), 3.02 (septet, J=7.07 Hz, 1H), 7.23-7.32 (m, 3H), 7.60-7.67 (m, 2H),11.81 (bs, 1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Iodo-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-Iodo-3-isopropyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

To a solution of 4-iodo-5-isopropyl-3-phenyl-1H-pyrazole (0.35 g, 1.121mmol) in DMF (5 mL) was added sodium hydride (0.027 g, 1.121 mmol) atroom temperature. The reaction was stirred at room temperature for 1 hand tert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(0.463 g, 1.121 mmol) was added. The reaction was heated at 50° C. for16 h, cooled to room temperature, and quenched with water (2 mL). Themixture was extracted with EtOAc. The organic extract was dried overMgSO₄ and concentrated. The residue was purified by silica gel columnchromatography to give the title compound (a mixture of tworegioisomers) as a clear liquid (0.52 g). LCMS m/z=553.2 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 0.99-1.20 (m, 4H), 1.25-1.42 (m, 4H), 1.46 (d,J=7.20 Hz, 6H), 1.48 (s, 9H), 1.82-1.94 (m, 1H), 2.07-2.19 (m, 1H),3.16-3.28 (m, 1H), 3.45 (d, J=7.07 Hz, 2H), 3.95 (s, 2H), 4.07 (d,J=7.71 Hz, 2H), 7.30-7.46 (m, 3H), 7.63-7.79 (m, 2H).

Step D: Preparation of2-(((1s,4s)-4-((3-Isopropyl-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

A mixture of phenylboronic acid (21.9 mg, 0.18 mmol), tert-butyl2-(((1s,4s)-4-((4-iodo-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-3-isopropyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.18 mmol),tetrakis(triphenylphosphine)palladium (10.0 mg, 0.009 mmol), K₂CO₃ (2 Maq., 0.2 mL) and dioxane (4 mL) was heated to 150° C. under microwaveirradiation for 4 h. The mixture was filtered and concentrated. Theresidue was treated with HCl (4 M in dioxane, 5 mL) at room temperaturefor 10 h. The mixture was concentrated and purified by HPLC to give thetitle compound (one of the two regioisomers separated) as a white solid(15.5 mg).

LCMS m/z=447.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05-1.15 (m,4H), 1.17 (d, J=6.82 Hz, 6H), 1.21-1.35 (m, 4H), 1.55-1.63 (m, 1H),1.84-1.95 (m, 1H), 2.96-3.04 (m, 1H), 3.20 (d, J=6.82 Hz, 2H), 3.91 (s,2H), 3.93 (d, J=7.58 Hz, 2H), 7.05-7.10 (m, 2H), 7.12-7.19 (m, 2H),7.19-7.27 (m, 3H), 7.32-7.40 (m, 3H).

Example 1.162: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 115)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.152. LCMS m/z=467.2[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.08-1.23 (m, 4H), 1.21 (t, J=7.58Hz, 3H), 1.27-1.45 (m, 4H), 1.68-1.79 (m, 1H), 1.94-2.04 (m, 1H), 2.77(q, J=7.54 Hz, 2H), 3.31 (d, J=6.57 Hz, 2H), 4.02 (s, 2H), 4.12 (d,J=7.58 Hz, 2H), 6.88-6.95 (m, 2H), 7.06-7.23 (m, 5H), 7.35-7.44 (m, 2H).

Example 1.163: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 116)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.152. LCMS m/z=467.2[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.13 (t, J=7.52 Hz, 3H), 1.32-1.46(m, 4H), 1.48-1.66 (m, 4H), 1.87-1.99 (m, 1H), 2.13-2.26 (m, 1H), 2.66(q, J=7.58 Hz, 2H), 3.52 (d, J=6.69 Hz, 2H), 4.10 (s, 2H), 4.17 (d,J=7.45 Hz, 2H), 7.02-7.08 (m, 2H), 7.18-7.38 (m, 7H).

Example 1.164: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 117)

From tert-butyl2-(((1s,4s)-4-((4-iodo-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-3-isopropyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2,3-difluorophenylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.161. LCMSm/z=483.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (d, J=7.07 Hz,6H), 1.20-1.36 (m, 8H), 1.56-1.64 (m, 1H), 1.87-1.97 (m, 1H), 2.78-2.88(m, 1H), 3.20 (d, J=7.07 Hz, 2H), 3.91 (s, 2H), 3.98 (d, J=7.58 Hz, 2H),6.96-7.14 (m, 2H), 7.19-7.26 (m, 3H), 7.32-7.41 (m, 3H).

Example 1.165: Preparation of2-(((1s,4s)-4-((5-(Ethylthio)-4-(2-fluorophenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 118)

From tert-butyl2-(((1s,4s)-4-((5-(ethylthio)-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-(ethylthio)-4-iodo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.149. LCMS m/z=483.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95 (t, J=7.33 Hz, 3H),1.32-1.56 (m, 8H), 1.72-1.82 (m, 1H), 2.17-2.28 (m, 1H), 2.53 (q, J=7.33Hz, 2H), 3.42 (d, J=6.82 Hz, 2H), 4.01 (s, 2H), 4.30 (d, J=7.58 Hz, 2H),7.20-7.30 (m, 5H), 7.32-7.39 (m, 2H), 7.40-7.49 (m, 2H).

Example 1.166: Preparation of2-(((1s,4s)-4-((5-(Ethylthio)-4-(3-fluoro-5-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 119)

From tert-butyl2-(((1s,4s)-4-((5-(ethylthio)-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-(ethylthio)-4-iodo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluoro-5-methoxyphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.149. LCMSm/z=513.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.99 (t, J=7.33 Hz,3H), 1.33-1.56 (m, 8H), 1.72-1.82 (m, 1H), 2.17-2.27 (m, 1H), 2.57 (q,J=7.33 Hz, 2H), 3.42 (d, J=6.82 Hz, 2H), 3.73:(s, 3H), 4.01 (s, 2H),4.28 (d, J=7.58 Hz, 2H), 6.62-6.70 (m, 2H), 6.76-6.83 (m, 1H), 7.23-7.41(m, 5H).

Example 1.167: Preparation of2-(((1s,4s)-4-((5-Cyclopropyl-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 120) Step A: Preparation of5-Cyclopropyl-3-phenyl-1H-pyrazole

To a solution of acetophenone (5.0 g, 41.6 mmol) in dry toluene (5 mL)was added LiHMDS (42.0 mL, 1.0 M in THF, 42.0 mmol) via syringe at 0° C.under argon. After 5 min, cyclopropanecarbonyl chloride (4.35 g, 41.6mmol) was added in one portion via syringe. The ice bath was removed andAcOH (2 mL), EtOH (50 mL), and hydrazine hydrate (10 mL, 64% aq., 127.8mmol) was added. The mixture was refluxed for 30 min, cooled to roomtemperature, and concentrated. The residue was extracted with EtOAc,washed with brine, dried over MgSO₄, and purified by silica gel columnchromatography to give the title compound as colorless oil (4.5 g).

LCMS m/z=184.7 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.71-0.80 (m, 2H),0.89-1.00 (m, 2H), 1.81-1.98 (m, 1H), 6.22 (s, 1H), 7.11-7.56 (m, 5H),10.50 (bs, 1H).

Step B: Preparation of 5-Cyclopropyl-4-iodo-3-phenyl-1H-pyrazole

To a solution of 5-cyclopropyl-3-phenyl-1H-pyrazole (3.0 g, 16.28 mmol)in THF (20 mL) and water (20 mL) were added sodium iodide (2.441 g,16.28 mmol), iodine (6.20 g, 24.43 mmol), and potassium carbonate (3.38g, 24.43 mmol) at room temperature. The reaction was brought to refluxfor 2 h at 100° C. The reaction was cooled to room temperature andquenched with 10% aq. Na₂SO₃. The organic solvent was removed underreduced pressure and the aqueous was extracted with EtOAc, washed withNaHCO₃ solution, brine, dried over MgSO₄, and concentrated. The residuewas purified by silica gel column chromatography to give the titlecompound (2.7 g). LCMS m/z=310.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.75-0.81 (m, 2H), 0.83-0.88 (m, 2H), 2.46-2.56 (m, 1H), 7.33-7.47 (m,3H), 7.62-7.71 (m, 2H), 12.91 (s, 1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((3-Cyclopropyl-4-iodo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((5-Cyclopropyl-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

A solution of 5-cyclopropyl-4-iodo-3-phenyl-1H-pyrazole (3.5 g, 11.29mmol) in DMF (5 mL) was treated with sodium hydride (0.271 g, 11.29mmol) at room temperature for 1 h, then tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (4.66 g, 11.29mmol) was added. The reaction mixture was heated to 50° C. for 16 h andquenched by water (2 mL). The mixture was extracted by EtOAc, dried overMgSO₄, and concentrated. The residue was purified by silica gel columnchromatography to give the title compound (a mixture of tworegioisomers) as colorless oil (4.5 g). LCMS m/z=551.1 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 1.04-1.19 (m, 4H), 1.33-1.44 (m, 4H), 1.46 (s,9H), 1.47 (d, J=8.08 Hz, 4H), 1.67-1.77 (m, 1H), 1.85-1.91 (m, 1H),1.90-1.99 (m, 1H), 3.25 (d, J=7.07 Hz, 2H), 3.87 (s, 2H), 3.91 (d,J=7.58 Hz, 2H), 7.28-7.54 (m, 5H).

Step D: Preparation of2-(((1s,4s)-4-((5-Cyclopropyl-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

A mixture of 3-methoxyphenylboronic acid (27.4 mg, 0.18 mmol),tert-butyl2-(((1s,4s)-4-((3-cyclopropyl-4-iodo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-cyclopropyl-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.18 mmol),tetrakis(triphenylphosphine)palladium (10.0 mg, 0.009 mmol), K₂CO₃ (2 Maq., 0.2 mL) and dioxane (4 mL) was heated to 150° C. under microwaveirradiation for 4 h. The mixture was filtered and concentrated. Theresidue was treated with HCl (4 M in dioxane, 5 mL) at room temperaturefor 10 h. The mixture was concentrated and purified by HPLC to give thetitle compound (one of the two regioisomers separated) as white solid(23.5 mg). LCMS m/z=475.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm0.35-0.48 (m, 2H), 0.86-0.99 (m, 2H), 1.44-1.80 (m, 8H), 1.83-2.01 (m,1H), 2.29-2.41 (m, 1H), 2.67-2.76 (m, 1H), 3.57 (d, J=6.95 Hz, 2H), 3.74(s, 3H), 4.13 (s, 2H), 4.30 (d, J=7.33 Hz, 2H), 6.70-7.00 (m, 4H),7.17-7.55 (m, 5H).

Example 1.168: Preparation of2-(((1s,4s)-4-((5-Cyclopropyl-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 122)

From tert-butyl2-(((1s,4s)-4-((3-cyclopropyl-4-iodo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-cyclopropyl-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and phenylboronic acid, the title compound(one of the two regioisomers separated) was obtained using a similarmethod to the one described in Example 1.167. LCMS m/z=445.4 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.20-0.27 (m, 2H), 0.74-0.81 (m, 2H),1.36-1.56 (m, 8H), 1.70-1.81 (m, 1H), 1.81-1.91 (m, 1H), 2.13-2.28 (m,1H), 3.42 (d, J=6.95 Hz, 2H), 4.00 (s, 2H), 4.17 (d, J=7.45 Hz, 2H),7.16-7.25 (m, 5H), 7.25-7.37 (m, 5H).

Example 1.169: Preparation of2-(((1s,4s)-4-((3-Isopropyl-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 123)

From tert-butyl2-(((1s,4s)-4-((4-iodo-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-3-isopropyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers, and 3-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.161. LCMS m/z=477.3[M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.10-1.26 (m, 4H), 1.29 (d, J=6.95Hz, 6H), 1.30-1.45 (m, 4H), 1.66-1.76 (m, 1H), 1.95-2.06 (m, 1H),3.10-3.22 (m, 1f), 3.29 (d, J=6.95 Hz, 2H), 3.66 (s, 3H), 4.00 (s, 2H),4.10 (d, J=7.71 Hz, 2H), 6.60-6.81 (m, 3H), 7.13-7.31 (m, 3H), 7.33-7.46(m, 3H).

Example 1.170: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-3-isopropyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 124)

From tert-butyl2-(((1s,4s)-4-((4-iodo-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-3-isopropyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.161. LCMS m/z=481.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (d, J=6.82 Hz, 6H),1.21-1.35 (m, 4H), 1.37-1.56 (m, 4H), 1.83-1.95 (m, 1H), 2.06-2.17 (m,1H), 2.96-3.06 (m, 1H), 3.20 (d, J=7.07 Hz, 2H), 3.91 (s, 2H), 3.93 (d,J=7.83 Hz, 2H), 7.01-7.09 (m, 1H), 7.15-7.31 (m, 5H), 7.35-7.44 (m, 3H).

Example 1.171: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-3-methoxyphenyl)-3-isopropyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 125)

From tert-butyl2-(((1s,4s)-4-((4-iodo-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-3-isopropyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluoro-3-methoxyphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.161. LCMSm/z=495.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24 (d, J=6.82 Hz,6H), 1.25-1.33 (m, 4H), 1.34-1.43 (m, 4H), 1.72-1.82 (m, 1H), 2.07-2.15(m, 1H), 2.98-3.08 (m, 1H), 3.42 (d, J=6.82 Hz, 2H), 3.77 (s, 3H), 3.99(s, 2H), 4.01 (d, J=7.59 Hz, 2H), 6.81-6.88 (m, 1H), 6.96-7.04 (m, 2H),7.22-7.30 (m, 2H), 7.32-7.40 (m, 3H).

Example 1.172: Preparation of2-(((1s,4s)-4-((5-Cyclopropyl-4-(2-fluoro-3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 126)

From tert-butyl2-(((1s,4s)-4-((3-cyclopropyl-4-iodo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-cyclopropyl-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluoro-3-methoxyphenylboronic acid,the title compound was obtained using a similar method to the onedescribed in Example 1.167. LCMS m/z=493.3 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 0.38-0.45 (m, 2H), 0.82-0.90 (m, 2H), 1.49-1.71 (m, 8H),1.82-1.90 (m, 1H), 1.90-2.00 (m, 1H), 2.29-2.40 (m, 1H), 3.57 (d, J=6.95Hz, 2H), 3.93 (s, 3H), 4.13 (s, 2H), 4.31 (d, J=7.58 Hz, 2H), 6.66-6.77(m, 2H), 7.01-7.15 (m, 3H), 7.22-7.39 (m, 3H).

Example 1.173: Preparation of2-(((1s,4s)-4-((5-Cyclopropyl-4-(2,3-difluorophenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 127)

From tert-butyl2-(((1s,4s)-4-((3-cyclopropyl-4-iodo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-cyclopropyl-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2,3-difluorophenylboronic acid, thetitle compound was obtained using a similar method to the one describedin Example 1.167. LCMS m/z=481.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm0.36-0.42 (m, 2H), 0.85-0.94 (m, 2H), 1.48-1.72 (m, 8H), 1.84-1.91 (m,1H), 1.89-1.97 (m, 1H), 2.29-2.40 (m, 1H), 3.56 (d, J=6.95 Hz, 2H), 4.12(s, 2H), 4.31 (d, J=7.70 Hz, 2H), 6.92-7.04 (m, 2H), 7.09-7.19 (m, 2H),7.19-7.40 (m, 4H).

Example 1.174: Preparation of2-(((1s,4s)-4-((5-Isopropyl-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 128)

From tert-butyl2-(((1s,4s)-4-((4-iodo-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-3-isopropyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.161. LCMS m/z=477.3[M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.23 (d, J=7.07 Hz, 6H), 1.44-1.75(m, 8H), 1.90-2.00 (m, 1H), 2.17-2.27 (m, 1H), 3.19-3.30 (m, 1H), 3.58(d, J=7.07 Hz, 2H), 3.78 (s, 3H), 4.13 (s, 2H), 4.17 (d, J=7.58 Hz, 2H),6.78-6.97 (m, 3H), 7.20-7.25 (m, 3H), 7.27-7.37 (m, 3H).

Example 1.175: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 129)

From tert-butyl2-(((1s,4s)-4-((4-iodo-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-3-isopropyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.161. LCMS m/z=481.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09 (d, J=7.07 Hz, 6H),1.34-1.57 (m, 8H), 1.74-1.83 (m, 1H), 2.06-2.17 (m, 1H), 2.95-3.05 (m,1H), 3.43 (d, J=7.07 Hz, 2H), 3.99 (s, 2H), 4.07 (d, J=7.33 Hz, 2H),7.01-7.08 (m, 1H), 7.12-7.27 (m, 4H), 7.32-7.54 (m, 4H).

Example 1.176: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-3-methoxyphenyl)-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 130)

From tert-butyl2-(((1s,4s)-4-((4-iodo-5-isopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-3-isopropyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluoro-3-methoxyphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.161. LCMSm/z=495.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12 (d, J=7.07 Hz,6H), 1.39-1.55 (m, 8H), 1.70-1.82 (m, 1H), 1.86-1.97 (m, 1H), 2.75-2.85(m, 1H), 3.20 (d, J=7.07 Hz, 2H), 3.77 (s, 3H), 3.91 (s, 2H), 3.96 (d,J=7.83 Hz, 2H), 6.97-7.05 (m, 1H), 7.13-7.30 (m, 4H), 7.31-7.40 (in,3H).

Example 1.177: Preparation of Methyl2-(((1s,4s)-4-((5-(Methylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)Methoxy)acetate (Compound 131)

From tert-butyl2-(((1s,4s)-4-((4-iodo-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand phenylboronic acid, the title compound (one of the two regioisomersseparated) was obtained using a similar method to the one described inExample 1.151. LCMS m/z=451.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.32-1.53 (m, 8H), 1.70-1.80 (m, 1H), 2.12 (s, 3H), 2.15-2.25 (m, 1H),3.39 (d, J=6.95 Hz, 2H), 3.80 (s, 2H), 4.28 (d, J=7.45 Hz, 2H),7.22-7.29 (m, 5H), 7.30-7.43 (m, 5H).

Example 1.178: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-3-cyclopropyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 132)

From tert-butyl2-(((1s,4s)-4-((3-cyclopropyl-4-iodo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-cyclopropyl-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.167. LCMS m/z=479.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.54-0.62 (m, 4H), 0.76-0.92 (m,4H), 0.95-1.10 (m, 4H), 1.30-1.41 (m, 1H), 1.53-1.60 (m, 1H), 1.60-1.69(m, 1H), 2.95 (d, J=6.82 Hz, 2H), 3.61 (d, J=7.33 Hz, 2H), 3.67 (s, 2H),6.85-6.93 (m, 2H), 6.95-7.07 (m, 4H), 7.08-7.23 (m, 3H).

Example 1.179: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-cyclopropyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 133)

From tert-butyl2-(((1s,4s)-4-((3-cyclopropyl-4-iodo-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-cyclopropyl-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.167. LCMS m/z=479.3[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.34-0.41 (m, 2H), 0.87-0.95 (m,2H), 1.37-1.65 (m, 8H), 1.71-1.80 (m, 1H), 1.88-1.97 (m, 1H), 2.23-2.33(m, 1H), 3.53 (d, J=6.95 Hz, 2H), 4.11 (s, 2H), 4.31 (d, J=7.58 Hz, 2H),7.00-7.05 (m, 1H), 7.19-7.30 (m, 6H), 7.30-7.36 (m, 2H).

Example 1.180: Preparation of Methyl2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)Methoxy)acetate (Compound 136)

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.19 mmol) in dioxane (3 mL) wereadded 3-methoxyphenylboronic acid (28.9 mg, 0.19 mmol),tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol), and K₂CO₃ (2M aq., 0.2 mL). The reaction was heated to 150° C. under microwaveirradiation for 4 h. The reaction mixture was filtered and concentrated.The residue was treated with HCl (4.0 M in dioxane, 5 mL) at roomtemperature for 10 h. The mixture was concentrated and purified by HPLCto give2-(((1s,4s)-4-((4-(3-methoxyphenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid. The title compound (15.4 mg) was obtained by treating the aboveacid with anhydrous methanol for 1 h.

LCMS m/z=463.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.53 (m,8H), 1.69-1.80 (m, 1H), 2.03-2.13 (m, 1H), 2.21 (s, 3H), 3.36 (d, J=7.07Hz, 2H), 3.56 (s, 3H), 3.68 (s, 3H), 3.82 (s, 2H), 4.04 (d, J=7.45 Hz,2H), 6.67-6.75 (m, 2H), 6.83-6.88 (m, 1H), 7.20-7.30 (m, 4H), 7.30-7.35(m, 2H).

Example 1.181: Preparation of2-(((1s,4s)-4-((3-(4-Fluorophenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 137)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 4-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.107. LCMS m/z=437.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35-1.53 (m, 8H), 1.72-1.81 (m,1H), 2.05-2.13 (m, 1H), 2.20 (s, 3H), 3.42 (d, J=6.95 Hz, 2H), 3.99 (s,2H), 4.05 (d, J=7.58 Hz, 2H), 7.03-7.18 (m, 4H), 7.25-7.42 (m, 5H).

Example 1.182: Preparation of2-(((1s,4s)-4-((3-(4-Chlorophenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 138)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 4-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.107. LCMS m/z=453.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.53 (m, 8H), 1.71-1.82 (m,1H), 2.03-2.14 (m, 1H), 2.20 (s, 3H), 3.42 (d, J=6.95 Hz, 2H), 3.99 (s,2H), 4.05 (d, J=7.45 Hz, 2H), 7.13-7.19 (m, 3H), 7.28-7.34 (m, 3H),7.35-7.41 (m, 3H).

Example 1.183: Preparation of2-(((1s,4s)-4-((5-Methyl-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 139)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and p-tolylboronic acid, the title compound(one of the two regioisomers separated) was obtained using a similarmethod to the one described in Example 1.107. LCMS m/z=433.3[M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.35-1.53 (m, 8H), 1.72-1.80 (m, 1H),2.04-2.13 (m, 1H), 2.19 (s, 3H), 2.25 (s, 3H), 3.42 (d, J=6.95 Hz, 2H),3.99 (s, 2H), 4.03 (d, J=7.45 Hz, 2H), 7.00-7.07 (m, 2H), 7.11-7.22 (m,4H), 7.24-7.40 (m, 3H).

Example 1.184: Preparation of2-(((1s,4s)-4-((3-(4-Methoxyphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 140)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 4-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.107. LCMS m/z=449.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.53 (m, 8H), 1.71-1.80 (m,1H), 2.04-2.14 (m, 1H), 2.19 (s, 3H), 3.42 (d, J=7.07 Hz, 2H), 3.71 (s,3H), 3.99 (s, 2H), 4.02 (d, J=7.45 Hz, 2H), 6.77-6.85 (m, 2H), 7.12-7.19(m, 2H), 7.18-7.41 (m, 5H).

Example 1.185: Preparation of2-(((1s,4s)-4-((3-(2,4-Difluorophenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yi)methyl)cyclohexyl)methoxy)aceticAcid (Compound 141)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2,4-difluorophenylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.107. LCMSm/z=454.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.53 (m, 8H),1.70-1.81 (m, 1H), 2.03-2.14 (m, 1H), 2.29 (s, 3H), 3.41 (d, J=6.95 Hz,2H), 3.99 (s, 2H), 4.07 (d, J=7.45 Hz, 2H), 7.04-7.08 (m, 2H), 7.08-7.24(m, 3H), 7.25-7.43 (m, 3H).

Example 1.186: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-5-(ethylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 142)

From tert-butyl2-(((s,4s)-4-((5-(ethylthio)-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand 2,3-difluoro-methoxyphenylboronic acid, the title compound (one ofthe two regioisomers separated) was obtained using a similar method tothe one described in Example 1.149. LCMS m/z=501.2 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.95 (t, J=7.33 Hz, 3H), 1.30-1.53 (m, 8H),1.69-1.81 (m, 1H), 2.15-2.27 (m, 1H), 2.56 (q, J=7.33 Hz, 2H), 3.38 (d,J=6.95 Hz, 2H), 3.75 (s, 2H), 4.29 (d, J=7.45 Hz, 2H), 7.14-7.21 (m,1H), 7.23-7.37 (m, 6H), 7.42-7.52 (m, 1H).

Example 1.187: Preparation of2-(((1s,4s)-4-((3-(2-Fluoro-4-methoxyphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 145)

From tert-butyl2-(((1s,4s)-4-((5-bromo-3-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((3-bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluoro-4-methoxyphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.107. LCMSm/z=467.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.53 (m, 8H),1.70-1.80 (m, 1H), 2.05-2.14 (m, 1H), 2.29 (s, 3H), 3.42 (d, J=6.82 Hz,2H), 3.66 (s, 3H), 3.99 (s, 2H), 4.07 (d, J=7.58 Hz, 2H), 6.79-6.91 (m,2H), 6.97-7.12 (m, 3H), 7.15-7.33 (m, 3H).

Example 1.188: Preparation of2-(((1s,4s)-4-((4-(5-Fluoropyridin-3-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 147)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 5-fluoropyridin-3-ylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.97. LCMSm/z=438.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.54 (m, 8H),1.70-1.81 (m, 1H), 2.02-2.14 (m, 1H), 2.27 (s, 3H), 3.42 (d, J=6.95 Hz,2H), 3.99 (s, 2H), 4.08 (d, J=7.58 Hz, 2H), 7.22-7.32 (m, 3H), 7.33-7.40(m, 1H), 7.54-7.61 (m, 1H), 7.69-7.74 (m, 1H), 8.18-8.23 (m, 1H), 8.50(d, J=2.78 Hz, 1H).

Example 1.189: Preparation of2-(((1s,4s)-4-((5-(Ethylthio)-4-(5-fluoropyridin-3-yl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 148)

From tert-butyl2-(((1s,4s)-4-((5-(ethylthio)-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand 5-fluoropyridin-3-ylboronic acid, the title compound (one of the tworegioisomers separated) was obtained using a similar method to the onedescribed in Example 1.149. LCMS m/z=484.2 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.95 (t, J=7.33 Hz, 3H), 1.34-1.54 (m, 8H), 1.70-1.81 (m,1H), 2.16-2.26 (m, 1H), 2.58 (q, J=7.33 Hz, 2H), 3.41 (d, J=6.95 Hz,2H), 4.00 (s, 2H), 4.30 (d, J=7.58 Hz, 2H), 7.27-7.35 (m, 5H), 7.65-7.71(m, 1H), 8.29 (t, J=1.64 Hz, 1H), 8.55 (d, J=2.78 Hz, 1H).

Example 1.190: Preparation of2-(((1s,4s)-4-((5-Ethyl-4-(5-fluoropyridin-3-yl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 149)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 5-fluoropyridin-3-ylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.152. LCMSm/z=452.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.07 (m, 3H),1.35-1.57 (m, 8H), 1.73-1.83 (m, 1H), 2.07-2.19 (m, 1H), 2.66 (q, J=7.49Hz, 2H), 3.44 (d, J=7.07 Hz, 2H), 4.00 (s, 2H), 4.06 (d, J=7.45 Hz, 2H),7.23-7.31 (m, 5H), 7.57-7.62 (m, 1H), 8.23 (t, J=1.71 Hz, 1H), 8.53 (d,J=2.78 Hz, 1H).

Example 1.191: Preparation of2-(((1s,4s)-4-((3,4-Diphenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 151) Step A: Preparation of3-Phenyl-5-(trifluoromethyl)-1H-pyrazole

To a stirred mixture of 4,4,4-trifluoro-1-phenylbutane-1,3-dione (5.0 g,23.13 mmol) in dry ethanol (100 mL) was added hydrazine hydrate (1.737g, 34.7 mmol) dropwise. The resulting solution was refluxed for 16 h.The reaction was cooled to room temperature and concentrated. The oilwas diluted with saturated NaHCO₃ solution and extracted with EtOAc,washed with brine, dried over MgSO₄ and concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a clear liquid which was crystallized in hexanes/ethyl acetate (3.25g).

LCMS m/z=213.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 6.77 (s, 1H),7.36-7.51 (m, 3H), 7.53-7.64 (m, 2H), 11.59 (s, 1H).

Step B: Preparation of 4-Iodo-3-phenyl-5-(trifluoromethyl)-1H-pyrazole

To a mixture of 3-phenyl-5-(trifluoromethyl)-1H-pyrazole (4.0 g, 18.85mmol) in THF (50 mL) and water (50 mL) were added sodium iodide (2.83 g,18.85 mmol), iodine (7.18 g, 28.3 mmol), and K₂CO₃ (2.61 g, 18.85 mmol)at room temperature. The reaction was refluxed for 16 h, quenched withsodium thiosulfite (2.0 M aq. 10 mL) and concentrated under reducedpressure. The reaction was extracted with ethyl acetate and washed withNaHCO₃, brine, dried over MgSO₄ and concentrated under reduced pressure.The residue was purified by silica gel column chromatography to give thetitle compound as white solid (4.0 g). LCMS m/z=338.8 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.39-7.62 (m, 3H), 7.70-7.75 (m, 1H), 7.82-7.88(m, 1H), 14.11 (s, 1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Iodo-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-Iodo-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

To a solution of 4-iodo-3-phenyl-5-(trifluoromethyl)-1H-pyrazole (2.0 g,5.92 mmol) in DMF (6 mL) was added sodium hydride (0.14 g, 5.92 mmol) inportions at 0° C. The reaction was stirred at that temperature for 1 hand tert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(2.44 g, 5.92 mmol) was added. The reaction was gently heated to 60° C.for 16 h, quenched with water (2 mL), extracted with ethyl acetate,dried over MgSO₄, and concentrated. The residue was purified by silicagel column chromatography to give the title compound (a mixture of tworegioisomers) as a colorless liquid (2.7 g). LCMS m/z=579.1 [M+H]⁺.

Step D: Preparation of2-(((1s,4s)-4-((3,4-Diphenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

In a solution of tert-butyl2-(((1s,4s)-4-((4-iodo-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.17 mmol) in dioxane (3 mL) wereadded phenylboronic acid (21.0 mg, 0.17 mmol),tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol), and K₂CO₃ (2M aq., 0.2 mL). The reaction was heated to 150° C. under microwaveirradiation for 4 h. The reaction mixture was filtered and concentrated.The residue was treated with HCl (4.0 M in dioxane, 4 mL) at roomtemperature for 10 h. The mixture was concentrated and purified by HPLCto give the title compound as a white solid (16.4 mg). LCMS m/z=473.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35-1.54 (m, 8H), 1.73-1.82 (m,1H), 2.13-2.21 (m, 1H), 3.42 (d, J=7.07 Hz, 2H), 3.99 (s, 2H), 4.27 (d,J=7.45 Hz, 2H), 7.23-7.29 (m, 5H), 7.37-7.43 (m, 5H), 12.30-12.76 (m,1H).

Example 1.192: Preparation of2-(((1s,4s)-4-((3-Phenyl-4-p-tolyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 152)

From tert-butyl2-(((s,4s)-4-((4-iodo-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and p-tolylboronic acid, the title compound(one of the two regioisomers separated) was obtained using a similarmethod to the one described in Example 1.191. LCMS m/z=487.2 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.54 (m, 8H), 1.73-1.83 (m, 1H),2.12-2.21 (m, 1H), 2.34 (s, 3H), 3.42 (d, J=7.07 Hz, 2H), 3.99 (s, 2H),4.26 (d, J=7.45 Hz, 2H), 7.09-7.15 (m, 2H), 7.18-7.23 (m, 2H), 7.23-7.30(m, 5H), 12.47 (s, 1H).

Example 1.193: Preparation of2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 154)

From tert-butyl2-(((1s,4s)-4-((4-iodo-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.191. LCMS m/z=503.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01-1.22 (m, 4H), 1.23-1.41 (m,4H), 1.54-1.70 (m, 1H), 1.86-2.02 (m, 1H), 3.15 (d, J=6.82 Hz, 2H), 3.49(s, 2H), 3.62 (s, 3H), 4.03 (d, J=7.07 Hz, 2H), 6.63-6.87 (m, 4H),7.13-7.24 (m, 2H), 7.29-7.53 (m, 3H).

Example 1.194: Preparation of2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 155)

From tert-butyl2-(((1s,4s)-4-((4-iodo-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.191. LCMS m/z=503.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.53 (m, 8H), 1.69-1.82 (m,1H), 2.11-2.19 (m, 1H), 3.35 (d, J=7.58 Hz, 2H), 3.53 (s, 2H), 3.71 (s,3H), 4.26 (d, J=7.96 Hz, 2H), 6.77-6.83 (m, 2H), 6.94-7.01 (m, 2H),7.22-7.35 (m, 5H).

Example 1.195: Preparation of2-(((1s,4s)-4-((5-Ethyl-4-(3-hydroxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 172)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-hydroxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.152. LCMS m/z=449.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (t, J=7.45 Hz, 3H),1.31-1.56 (m, 8H), 1.69-1.83 (m, 1H), 2.03-2.19 (m, 1H), 2.58 (q, J=7.41Hz, 2H), 3.40 (d, J=7.07 Hz, 2H), 3.79 (s, 2H), 4.01 (d, J=7.58 Hz, 2H),6.54-6.63 (m, 2H), 6.67-6.75 (m, 1H), 7.09-7.38 (m, 6H).

Example 1.196: Preparation of2-(((1s,4s)-4-((4-(3-Hydroxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 173)

From tert-butyl2-(((1s,4s)-4-((4-iodo-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand phenylboronic acid, the title compound (one of the two regioisomersseparated) was obtained using a similar method to the one described inExample 1.151. LCMS m/z=467.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.31-1.53 (m, 8H), 1.70-1.80 (m, 1H), 2.13 (s, 3H), 2.15-2.25 (m, 1H),3.38 (d, J=7.07 Hz, 2H), 3.80 (s, 2H), 4.26 (d, J=7.33 Hz, 2H),6.63-6.78 (m, 3H), 7.13-7.20 (m, 1H), 7.21-7.30 (m, 3H), 7.33-7.38 (m,2H).

Example 1.197: Preparation of2-(((1s,4s)-4-((5-(Ethylthio)-4-(2-fluoro-3-hydroxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 174)

From tert-butyl2-(((1s,4s)-4-((5-(ethylthio)-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand 2-fluoro-3-hydroxyphenylboronic acid, the title compound (one of thetwo regioisomers separated) was obtained using a similar method to theone described in Example 1.149. LCMS m/z=499.2 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.97 (t, J=7.33 Hz, 3H), 1.31-1.53 (m, 8H), 1.68-1.81 (m,1H), 2.14-2.25 (m, 1H), 2.54 (q, J=7.33 Hz, 2H), 3.38 (d, J=6.82 Hz,2H), 3.74 (s, 2H), 4.27 (d, J=7.33 Hz, 2H), 6.64-6.73 (m, 1H), 6.95-7.06(m, 2H), 7.19-7.30 (m, 2H), 7.34-7.40 (m, 2H), 7.41-7.53 (m, 1H).

Example 1.198: Preparation of2-(((1s,4s)-4-((5-(Ethylthio)-4-(3-hydroxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 177)

From tert-butyl 2-(((ls,4s)-4-((5-(ethylthio)-4-iodo-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand 3-hydroxyphenylboronic acid, the title compound (one of the tworegioisomers separated) was obtained using a similar method to the onedescribed in Example 1.149. LCMS m/z=489.2 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.97 (t, J=7.33 Hz, 3H), 1.31-1.53 (m, 8H), 1.70-1.81 (m,1H), 2.14-2.25 (m, 1H), 2.53 (q, J=7.33 Hz, 2H), 3.41 (d, J=7.07 Hz,2H), 4.00 (s, 2H), 4.26 (d, J=7.58 Hz, 2H), 6.63-6.76 (m, 2H), 7.14-7.21(m, 2H), 7.21-7.30 (m, 3H), 7.32-7.39 (m, 2H).

Example 1.199: Preparation of2-(((1s,4s)-4-((4-(3-Hydroxyphenyl)-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 180) Step A: Preparation of5-(2-Methoxyethyl)-3-phenyl-1H-pyrazole

To a solution of acetophenone (3.5 g, 29.1 mmol) in dry toluene (10 mL)was added LiHMDS (1.0 M in toluene) via syringe at 0° C. under argon.After 5 min, 3-methoxypropanoyl chloride (3.57 g, 29.1 mmol) was addedin one portion via syringe. The ice bath was removed and AcOH (2 mL),EtOH (100 mL), and hydrazine hydrate (4.37 g, 87 mmol) were added. Thereaction was refluxed for 2 h, cooled to room temperature, andconcentrated. The residue was extracted with EtOAc/H₂O, washed withbrine, dried over MgSO₄, and concentrated. The resulting residue waspurified by silica gel column chromatography to give the title compoundas pale yellow oil (2.0 g).

LCMS m/z=203.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.85 (bs, 2H),3.27 (s, 3H), 3.59 (t, J=6.82 Hz, 2H), 6.49 (s, 1H), 7.21-7.46 (m, 3H),7.74 (m, 2H), 12.56 (s, 1H).

Step B: Preparation of 4-Bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazole

To a solution of 5-(2-methoxyethyl)-3-phenyl-1H-pyrazole (2.0 g, 9.89mmol) in DCM (100 mL) was added bromine (4.74 g, 29.7 mmol) dropwise at0° C. The reaction was stirred at that temperature for 1 h and continuedat room temperature for 2 h before quenched with Na₂SO₃ (10% aq.). Theorganics were separated, and the aqueous layer was extracted with DCM(2×50 mL). The combined organics were washed with brine, dried overMgSO₄, and concentrated to give the title compound (2.5 g). LCMSm/z=281.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.87 (t, J 6.82 Hz,2H), 3.27 (s, 3H), 3.62 (t, J=6.82 Hz, 2H), 5.75 (s, 1H), 7.35-7.51 (m,3H), 7.75-7.82 (m, 2H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-Bromo-3-(2-methoxyethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

To a solution of 4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazole (3.0 g,10.67 mmol) in DMF (5 mL) was added sodium hydride (0.256 g, 10.67mmol), followed by tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (4.40 g, 10.67mmol). The reaction was gently heated to 45° C. overnight. Afterquenched with water (5 mL), the mixture was extracted with EtOAc, washedwith brine, dried over MgSO₄, and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound (amixture of two regioisomers, 4.5 g). LCMS m/z=523.4 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.69-1.80 (m, 4H), 1.81-1.89 (m, 4H), 1.91 (s, 9H),2.19-2.30 (m, 2H), 2.90 (s, 3H), 3.46 (t, J=6.63 Hz, 2H), 3.89 (d,J=6.95 Hz, 2H), 4.02 (t, J=6.32 Hz, 2H), 4.43 (s, 2H), 4.56 (d, J=7.45Hz, 2H), 7.81-7.99 (m, 311), 8.24-8.32 (m, 2H).

Step D: Preparation of2-(((1s,4s)-4-((4-(3-Hydroxyphenyl)-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-methoxyethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.192 mmol) in dioxane (3 mL) wereadded 3-hydroxyphenylboronic acid (26.5 mg, 0.192 mmol),tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol), and K₂CO₃ (2M aq., 0.2 mL). The reaction was heated to 150° C. under microwaveirradiation for 4 h. The reaction mixture was filtered and concentrated.The residue was treated with HCl (4.0 M in dioxane, 5 mL) at roomtemperature for 10 h. The mixture was concentrated and purified by HPLCto give the title compound (one of the two regioisomers separated) as awhite solid (12.8 mg). LCMS m/z=479.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.32-1.57 (m, 8H), 1.73-1.82 (m, 1H), 2.07-2.18 (m, 1H), 2.83 (t,J=6.95 Hz, 2H), 3.15 (s, 3H), 3.35 (t, J=6.95 Hz, 2H), 3.43 (d, J=7.07Hz, 2H), 4.00 (s, 2H), 4.05 (d, J=7.58 Hz, 2H), 6.56-6.75 (m, 3H),7.14-7.26 (m, 4H), 7.30-7.37 (m, 2H).

Example 1.200: Preparation of2-(((1s,4s)-4-((5-(2-Methoxyethyl)-4-(6-methoxypyridin-3-yl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 181)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-methoxyethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 6-methoxypyridin-3-ylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.199. LCMSm/z=494.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.57 (m, 8H),1.74-1.84 (m, 1H), 2.09-2.18 (m, 1H), 2.83 (t, J=6.69 Hz, 2H), 3.16 (s,3H), 3.38 (t, J=6.69 Hz, 2H), 3.43 (d, J=7.07 Hz, 2H), 3.87 (s, 3H),4.00 (s, 2H), 4.06 (d, J=7.33 Hz, 2H), 6.83 (d, J=8.59 Hz, 1H),7.19-7.33 (m, 5H), 7.51 (dd, J=8.46, 2.40 Hz, 1H), 8.01 (d, J=2.02 Hz,1H).

Example 1.201: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-3-hydroxyphenyl)-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 182)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-methoxyethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluoro-3-hydroxyphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.199. LCMSm/z=497.2 [M+H]⁺; 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.54 (m, 8H),1.72-1.84 (m, 1H), 2.06-2.19 (m, 1H), 2.79 (t, J=6.32 Hz, 2H), 3.12 (s,3H), 3.31 (t, J=6.95 Hz, 2H), 3.40 (d, J=6.82 Hz, 2H), 3.68 (s, 2H),4.07 (d, J=7.07 Hz, 2H), 6.59-6.65 (m, 1H), 6.94-7.04 (m, 2H), 7.16-7.27(m, 3H), 7.31-7.37 (m, 2H).

Example 1.202: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 190)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-methoxyethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2,3-difluoro-phenylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.199. LCMSm/z=499.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.56 (m, 8H),1.71-1.83 (m, 1H), 2.07-2.19 (m, 1H), 2.83 (t, J=6.32 Hz, 2H), 3.11 (s,3H), 3.33 (t, J=6.57 Hz, 2H), 3.39 (d, J=6.82 Hz, 2H), 3.67 (s, 2H),4.09 (d, J=7.33 Hz, 2H), 7.10-7.18 (m, 1H), 7.19-7.33 (m, 6H), 7.38-7.48(m, 1H).

Example 1.203: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 191)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-methoxyethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chloro-2-fluorophenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.199. LCMSm/z=515.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28-1.55 (m, 8H),1.71-1.85 (m, 1H), 2.07-2.19 (m, 1H), 2.81 (t, J=5.68 Hz, 2H), 3.11 (s,3H), 3.32 (t, J=6.44 Hz, 2H), 3.40 (d, J=6.82 Hz, 2H), 3.68 (s, 2H),4.09 (d, J=7.33 Hz, 2H), 7.18-7.34 (m, 6H), 7.55-7.63 (m, 2H).

Example 1.204: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-3-methylphenyl)-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 192)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-methoxyethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluoro-3-methylphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.199. LCMSm/z=495.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.56 (m, 8H),1.72-1.83 (m, 1H), 2.06-2.17 (m, 1H), 2.23 (s, 3H), 2.78 (t, J=5.94 Hz,2H), 3.11 (s, 3H), 3.30 (t, J=6.06 Hz, 2H), 3.40 (d, J=6.57 Hz, 2H),3.71 (s, 2H), 4.07 (d, J=6.82 Hz, 2H), 7.05-7.16 (m, 3H), 7.16-7.34 (m,5H).

Example 1.205: Preparation of2-(((1s,4s)-4-((5-(2-Methoxyethyl)-3-phenyl-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 193)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-methoxyethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and m-tolylboronic acid, the title compound(one of the two regioisomers separated) was obtained using a similarmethod to the one described in Example 1.199. LCMS m/z=477.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.54 (m, 8H), 1.72-1.84 (m, 1H),2.06-2.18 (m, 1H), 2.28 (s, 3H), 2.82 (t, J=6.82 Hz, 2H), 3.14 (s, 3H),3.35 (t, J=6.82 Hz, 2H), 3.40 (d, J=7.07 Hz, 2H), 3.69 (s, 2H), 4.06 (d,J=7.33 Hz, 2H), 6.97 (d, J=7.58 Hz, 1H), 7.04 (s, 1H), 7.13 (d, J=7.58Hz, 1H), 7.17-7.35 (m, 6H).

Example 1.206: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 194)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-methoxyethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.199. LCMS m/z=481.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-ds) δ ppm 1.32-1.56 (m, 8H), 1.73-1.83 (m,1H), 2.07-2.18 (m, 1H), 2.87 (t, J=6.69 Hz, 2H), 3.15 (s, 3H), 3.37 (t,J=6.69 Hz, 2H), 3.41 (d, J=7.07 Hz, 2H), 3.83 (s, 2H), 4.07 (d, J=7.33Hz, 2H), 7.01-7.06 (m, 2H), 7.11-7.18 (m, 1H), 7.19-7.33 (m, 4H),7.37-7.45 (m, 2H).

Example 1.207: Preparation of2-(((1s,4s)-4-((4-(2-Methoxypyridin-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 195)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-methoxypyridin-4-ylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.97. LCMSm/z=450.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.54 (m, 8H),1.71-1.80 (m, 1H), 2.04-2.13 (m, 1H), 2.28 (s, 3H), 3.42 (d, J=7.07 Hz,2H), 3.85 (s, 3H), 3.99 (s, 2H), 4.06 (d, J=7.33 Hz, 2H), 6.62 (s, 1H),6.74 (dd, J=5.31, 1.26 Hz, 1H), 7.26-7.35 (m, 5H), 8.10 (d, J=5.31 Hz,1H).

Example 1.208: Preparation of2-(((1s,4s)-4-((5-Ethyl-4-(2-methoxypyridin-4-yl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 196)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-methoxypyridin-4-ylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.152. LCMSm/z=464.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (t, J=7.58 Hz,3H), 1.32-1.57 (m, 8H), 1.71-1.83 (m, 1H), 2.07-2.18 (m, 1H), 2.67 (q,J=7.49 Hz, 2H), 3.43 (d, J=6.82 Hz, 2H), 3.85 (s, 3H), 4.00 (s, 2H),4.04 (d, J=7.33 Hz, 2H), 6.61 (s, 1H), 6.76 (dd, J=5.31, 1.26 Hz, 1H),7.22-7.34 (m, 5H), 8.12 (d, J=5.31 Hz, 1H).

Example 1.209: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 197)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-methoxyethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.199. LCMS m/z=497.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.56 (m, 8H), 1.73-1.84 (m,1H), 2.06-2.18 (m, 1H), 2.86 (t, J=6.69 Hz, 2H), 3.15 (s, 3H), 3.37 (d,J=6.82 Hz, 2H), 3.39 (t, J=7.07 Hz, 2H), 3.75 (s, 2H), 4.06 (d, J=7.58Hz, 2H), 7.14-7.19 (m, 1H), 7.20-7.31 (m, 6H), 7.35-7.43 (m, 2H).

Example 1.210: Preparation of2-(((1s,4s)-4-((5-Ethyl-4-(5-methoxypyridin-3-yl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 201)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-ethyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-ethyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 5-methoxypyridin-3-ylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.152. LCMSm/z=464.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (t, J=7.52 Hz,3H), 1.36-1.58 (m, 8H), 1.74-1.83 (m, 1H), 2.10-2.19 (m, 1H), 2.67 (q,J=7.45 Hz, 2H), 3.44 (d, J=7.07 Hz, 2H), 3.84 (s, 3H), 4.00 (s, 2H),4.07 (d, J=7.45 Hz, 2H), 7.23-7.33 (m, 5H), 7.47 (dd, J=2.65, 1.64 Hz,1H), 8.09 (d, J=1.64 Hz, 1H), 8.38 (d, J=2.78 Hz, 1H).

Example 1.211: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-3-hydroxyphenyl)-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 213) Step A: Preparation of5-(2-(Methylthio)ethyl)-3-phenyl-1H-pyrazole

To a solution of acetophenone (5.0 g, 41.6 mmol) in dry toluene (10 mL)was added LiHMDS (1.0 M in toluene, 42 mL, 42 mmol) via syringe at 0° C.under argon. After 5 min, 3-(methylthio)propanoyl chloride (5.77 g, 41.6mmol) was added in one portion via syringe. The ice bath was removed andAcOH (5 mL), EtOH (100 mL), and hydrazine hydrate (6.25 g, 125 mmol)were added. The mixture was refluxed for 2 h, cooled to roomtemperature, and concentrated. The residue was extracted with EtOAcH₂O,washed with brine, dried over MgSO₄, and concentrated.

The resulting residue was purified by silica gel column chromatographyto give the title compound as a pale yellow oil (6.5 g). LCMS m/z=219.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.09 (s, 3H), 2.77 (t, J=7.71Hz, 2H), 2.84-2.95 (m, 2H), 6.53 (s, 1H), 7.18-7.50 (m, 3H), 7.63-7.84(m, 2H), 12.60 (bs, 1H).

Step B: Preparation of4-Bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazole

To a solution of 5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazole (4.0 g,18.32 mmol) in methanol (20 mL) was added N-bromosuccinimide (3.26 g,18.32 mmol) slowly at 0° C. The reaction was stirred at 0° C. for 2 h.The mixture was concentrated and purified by silica gel columnchromatography to give the title compound (3.4 g). LCMS m/z=297.0[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.11 (s, 3H), 2.79 (t, J=7.83Hz, 2H), 2.83-2.97 (m, 2H), 7.32-7.56 (m, 3H), 7.67-7.88 (m, 2H), 13.20(bs, 1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-Bromo-3-(2-(methylthio)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

To a solution of 4-bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazole(3.4 g, 11.44 mmol) in DMF (5 mL) was added sodium hydride (0.275 g,11.44 mmol) at room temperature, followed by tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (4.72 g, 11.44mmol). The reaction was heated to 45° C. overnight, cooled to roomtemperature, and quenched with water (5 mL). The mixture was extractedwith EtOAc, washed with brine, dried over MgSO₄, and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound (a mixture of two regioisomers, 3.5 g). LCMS m/z=539.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.40 (m, 4H), 1.43 (s, 9H),1.44-1.52 (m, 4H), 1.70-1.80 (m, 1H), 2.03-2.11 (m, 1H), 2.14 (s, 3H),2.72 (t, J=7.07 Hz, 2H), 3.00 (t, J=7.20 Hz, 2H), 3.40 (d, J=6.95 Hz,2H), 3.94 (s, 2H), 4.09 (d, J=7.45 Hz, 2H), 7.32-7.51 (m, 3H), 7.75-7.84(m, 2H).

Step D: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-3-hydroxyphenyl)-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-(methylthio)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.19 mmol) in dioxane were added2-fluoro-3-hydroxyphenylboronic acid (29.6 mg, 0.19 mmol),tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol), and K₂CO₃ (2M aq., 0.2 mL). The reaction was heated to 150° C. under microwaveirradiation for 4 h. The reaction mixture was filtered and concentrated.The residue was treated with HCl (4.0 M in dioxane, 5 mL) at roomtemperature for 10 h. The mixture was concentrated and purified by HPLCto give the title compound (one of the two regioisomers separated) as awhite solid (15.5 mg). LCMS m/z=513.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.32-1.57 (m, 8H), 1.74-1.82 (m, 1H), 1.88 (s, 3H), 2.08-2.18 (m,1H), 2.46 (t, J=7.71 Hz, 2H), 2.82 (t, J=7.20 Hz, 2H), 3.43 (d, J=7.07Hz, 2H), 4.00 (s, 2H), 4.08 (d, J=7.45 Hz, 2H), 6.65-6.72 (m, 1H),6.91-7.04 (m, 3H), 7.17-7.28 (m, 3H), 7.31-7.37 (m, 1H).

Example 1.212: Preparation of2-(((1s,4s)-4-((4-(5-Methoxypyridin-3-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 214)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers, and 5-methoxypyridin-3-ylboronic acid, thetitle compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.97. LCMSm/z=450.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35-1.55 (m, 8H),1.72-1.82 (m, 1H), 2.05-2.15 (m, 1H), 2.27 (s, 3H), 3.42 (d, J=7.07 Hz,2H), 3.81 (s, 3H), 4.00 (s, 2H), 4.08 (d, J=7.45 Hz, 2H), 7.23-7.33 (m,5H), 7.39 (dd, J=2.65, 1.64 Hz, 1H), 8.04 (d, J=1.52 Hz, 1H), 8.32 (d,J=2.78 Hz, 1H).

Example 1.213: Preparation of2-(((1s,4s)-4-((5-(2-(Methylthio)ethyl)-3-phenyl-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 216)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-(methylthio)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and m-tolylboronic acid, the title compound(one of the two regioisomers separated) was obtained using a similarmethod to the one described in Example 1.211. LCMS m/z=493.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.56 (m, 8H), 1.70-1.82 (m, 1H), 1.89(s, 3H), 2.07-2.16 (m, 1H), 2.29 (s, 3H), 2.50 (t, J=7.06 Hz, 2H), 2.86(t, J=7.33 Hz, 2H), 3.40 (d, J=6.80 Hz, 2H), 3.77 (s, 2H), 4.06 (d,J=7.45 Hz, 2H), 6.98 (d, J=7.71 Hz, 1H), 7.07 (s, 1H), 7.13 (d, J=7.58Hz, 1H), 7.17-7.28 (m, 4H), 7.29-7.35 (m, 2H).

Example 1.214: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-3-methylphenyl)-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 218)

From tert-butyl 2-(((ls,4s)-4-((4-bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-(methylthio)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluoro-3-methylphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.211. LCMSm/z=511.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.56 (m, 8H),1.73-1.81 (m, 1H), 1.85 (s, 3H), 2.09-2.17 (m, 1H), 2.23 (s, 3H), 2.46(t, J=7.71 Hz, 2H), 2.81 (t, J=7.07 Hz, 2H), 3.41 (d, J=6.95 Hz, 2H),3.81 (s, 2H), 4.08 (d, J=7.45 Hz, 2H), 7.07-7.14 (m, 2H), 7.18-7.26 (m,3H), 7.26-7.35 (m, 3H).

Example 1.215: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-5-(2-(methylsulfinyl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 219)

2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid (16.4 mg, 0.031 mmol) was dissolved in DCM (2 mL) and3-chloroperbenzoic acid (5.33 mg, 0.031 mmol) was added. After stirredat room temperature for 30 min, the reaction mixture was concentratedand purified by HPLC to give the title compound as a white solid (10.8mg). LCMS m/z=547.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.56(m, 8H), 1.74-1.82 (m, 1H), 2.10-2.20 (m, 1H), 2.46 (s, 3H), 2.66-2.77(m, 2H), 2.83-3.00 (m, 2H), 3.43 (d, J=7.07 Hz, 2H), 3.99 (s, 2H),4.08-4.14 (m, 2H), 7.20-7.30 (m, 6H), 7.30-7.36 (m, 1H), 7.56-7.64 (m,1H).

Example 1.216: Preparation of2-(((1s,4s)-4-((5-(2-(Methylsulfinyl)ethyl)-3-phenyl-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 220)

To a solution of2-(((1s,4s)-4-((5-(2-(methylthio)ethyl)-3-phenyl-4-m-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid (19.7 mg, 0.040 mmol) in DCM (2 mL) was added 3-chloroperbenzoicacid (6.9 mg, 0.040 mmol). After stirred at room temperature for 30 min,the reaction mixture was concentrated and purified by HPLC to give thetitle compound as a white solid (14.2 mg). LCMS m/z=509.2 [M+H]⁺; H NMR(400 MHz, DMSO-d₆) δ ppm 1.31-1.55 (m, 8H), 1.71-1.81 (m, 1H), 2.08-2.18(m, 1H), 2.27 (s, 3H), 2.44 (s, 3H), 2.68-2.79 (m, 2H), 2.82-2.99 (m,2H), 3.43 (d, J=7.07 Hz, 2H), 3.98 (s, 2H), 4.04-4.10 (m, 2H), 6.97 (d,J=7.58 Hz, 1H), 7.05 (s, 1H), 7.13 (d, J=7.58 Hz, 1H), 7.17-7.27 (m,4H), 7.28-7.33 (m, 2H).

Example 1.217: Preparation of2-(((1s,4s)-4-((4-(3-Hydroxyphenyl)-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 221)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-(methylthio)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-hydroxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.211. LCMS m/z=495.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.55 (m, 8H), 1.74-1.82 (m,1H), 1.91 (s, 3H), 2.09-2.16 (m, 1H), 2.51 (t, J=6.82 Hz, 2H), 2.86 (t,J=7.33 Hz, 2H), 3.43 (d, J=7.07 Hz, 2H), 4.00 (s, 2H), 4.06 (d, J=7.45Hz, 2H), 6.57-6.75 (m, 3H), 7.15-7.27 (m, 4H), 7.32-7.37 (m, 2H).

Example 1.218: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 222)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-(methylthio)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluorophenylboronic acid, the titlecompound was obtained using a similar method to the one described inExample 1.211. LCMS m/z=497.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.34-1.59 (m, 8H), 1.74-1.82 (m, 1H), 1.90 (s, 3H), 2.09-2.18 (m, 1H),2.52 (t, J=6.82 Hz, 2H), 2.91 (t, J=7.33 Hz, 2H), 3.44 (d, J=6.95 Hz,2H), 4.00 (s, 2H), 4.08 (d, J=7.45 Hz, 2H), 7.02-7.09 (m, 2H), 7.12-7.19(m, 1H), 7.19-7.33 (m, 5H), 7.38-7.47 (m, 1H).

Example 1.219: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 237)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-(methylthio)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.211. LCMS m/z=513.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35-1.55 (m, 8H), 1.74-1.82 (m,1H), 1.90 (s, 3H), 2.09-2.17 (m, 1H), 2.53 (t, J=7.20 Hz, 2H), 2.90 (t,J=7.45 Hz, 2H), 3.43 (d, J=7.07 Hz, 2H), 3.96 (s, 2H), 4.07 (d, J=7.45Hz, 2H), 7.15-7.19 (m, 2H), 7.22-7.32 (m, 5H), 7.37-7.41 (m, 2H).

Example 1.220: Preparation of2-(((1s,4s)-4-((5-(2-(Methylthio)ethyl)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 238)

From tert-butyl 2-(((Is,4s)-4-((4-bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-(methylthio)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and phenylboronic acid, the title compound(one of the two regioisomers separated) was obtained using a similarmethod to the one described in Example 1.211. LCMS m/z=479.2 [M+H]⁺;¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.56 (m, 8H), 1.73-1.81 (m, 1H),1.88 (s, 3H), 2.08-2.18 (m, 1H), 2.50 (t, J=7.33 Hz, 2H), 2.87 (t,J=7.33 Hz, 2H), 3.42 (d, J=7.07 Hz, 2H), 3.88 (s, 2H), 4.07 (d, J=7.45Hz, 2H), 7.16-7.25 (m, 5H), 7.28-7.41 (m, 5H).

Example 1.221: Preparation of2-(((1s,4s)-4-((5-(2-Fluoro-4-methylphenyl)-3-(2-methoxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 239) Step A: Preparation of5-(2-Methoxyethyl)-4-phenyl-1H-pyrazole

To a solution of 2-phenylacetaldehyde (4.0 g, 33.3 mmol) in toluene (10mL), were added LiHMDS (33.3 mL, 33.3 mmol) at 0° C. After stirring for10 min, 3-methoxypropanoyl chloride (4.08 g, 33.3 mmol) was added andcontinued stirring for 30 min at 0° C. The reaction was quenched withacetic acid (glacial, 2 mL), diluted with ethanol (75 mL), and hydrazinehydrate (5.00 g, 100 mmol) was added. The reaction was brought to refluxfor 4 hrs. After cooling to room temperature, the reaction wasconcentrated and extracted with EtOAc, dried over MgSO₄, and purified bycolumn chromatography to give the title compound as yellowish oil (2.5g). LCMS m/z=203.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.85 (t,J=6.69 Hz, 2H), 3.17 (s, 3H), 3.48 (t, J=6.63 Hz, 2H), 5.75 (s, 1H),7.31-7.38 (m, 3H), 7.41-7.47 (m, 2H), 13.08 (s, 1H).

Step B: Preparation of 3-Bromo-5-(2-methoxyethyl)-4-phenyl-1H-pyrazole

To a solution of 5-(2-methoxyethyl)-4-phenyl-1H-pyrazole (1.0 g, 4.94mmol) in methanol (20 mL) was added N-bromosuccinimide (0.880 g, 4.94mmol) in portions at room temperature. After stirred at room temperaturefor 16 h, the reaction was concentrated and extracted with EtOAc/H₂O,purified by column chromatography to give the title compound as yellowoil (1.0 g).

LCMS m/z=281.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.97 (t, J=6.63Hz, 2H), 3.22 (s, 3H), 3.57 (t, J=7.07 Hz, 2H), 7.20-7.27 (m, 2H),7.35-7.45 (m, 3H), 12.67 (bs, 1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((3-Bromo-5-(2-methoxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((5-Bromo-3-(2-methoxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

To a solution of 3-bromo-5-(2-methoxyethyl)-4-phenyl-1H-pyrazole (1.0 g,3.6 mmol) in DMF (5 mL) were added cesium carbonate (1.16 g, 3.6 mmol),followed by tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (1.47 g, 3.6mmol). The reaction was gently heated to 80° C. for 10 h. After cooledto room temperature, the reaction was quenched with water (2 mL),extracted with EtOAc, dried over MgSO₄, and purified by columnchromatography to give the title compound as clear oil. LCMS m/z=521.5[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.42 (m, 4H), 1.43 (s, 9H),1.44-1.52 (m, 4H), 1.70-1.81 (m, 1H), 2.04-2.14 (m, 1H), 2.91 (t, J=6.57Hz, 2H), 3.14 (s, 3H), 3.41 (d, J=6.95 Hz, 2H), 3.47 (t, J=7.20 Hz, 2H),3.95 (s, 2H), 4.04 (d, J=7.07 Hz, 2H), 7.32-7.39 (m, 3H), 7.40-7.50 (m,2H).

Step D: Preparation of2-(((1s,4s)-4-((5-(2-Fluoro-4-methylphenyl)-3-(2-methoxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((3-bromo-5-(2-methoxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-3-(2-methoxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.19 mmol) in dioxane (3 mL) wereadded 2-fluoro-4-methylphenylboronic acid (29.3 mg, 0.19 mmol),tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol), and K₂CO₃ (2M aq., 0.2 mL). The reaction was heated to 150° C. under microwaveirradiation for 4 h. After filtered and concentrated, the residue wastreated with HCl (4.0 M in dioxane, 5 mL) at room temperature for 10 h.The mixture was concentrated and purified by HPLC to give the titlecompound as white solid (15.6 mg). LCMS m/z=495.4 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.05-1.18 (m, 4H), 1.21-1.36 (m, 4H), 1.56-1.67 (m,1H), 1.85-1.97 (m, 1H), 2.33 (s, 3H), 2.84 (t, J=7.45 Hz, 2H), 3.18 (s,3H), 3.19 (d, J=7.07 Hz, 2H), 3.53 (t, J=7.39 Hz, 2H), 3.74 (s, 2H),3.81 (d, J=7.83 Hz, 2H), 7.03-7.13 (m, 5H), 7.13-7.20 (m, 2H), 7.22-7.28(m, 2H).

Example 1.222: Preparation of2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-5-(2-methoxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 240)

From tert-butyl2-(((1s,4s)-4-((3-bromo-5-(2-methoxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-3-(2-methoxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluoro-4-methylphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.221. LCMSm/z=495.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.55 (m, 8H),1.71-1.82 (m, 1H), 2.04-2.17 (m, 1H), 2.28 (s, 3H), 2.93 (t, J=6.82 Hz,2H), 3.16 (s, 3H), 3.40 (t, J=6.63 Hz, 2H), 3.41 (d, J=6.69 Hz, 2H),3.87 (s, 2H), 4.07 (d, J=7.45 Hz, 2H), 6.87-6.98 (m, 2H), 7.07-7.13 (m,2H), 7.16-7.31 (m, 5H).

Example 1.223: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-4-methylphenyl)-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 241)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-methoxyethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-methoxyethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluoro-4-methylphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.199. LCMSm/z=495.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.57 (m, 8H),1.73-1.83 (m, 1H), 2.08-2.18 (m, 1H), 2.36 (s, 3H), 2.78 (t, J=6.76 Hz,2H), 3.12 (s, 3H), 3.30 (t, J=6.82 Hz, 2H), 3.42 (d, J=7.07 Hz, 2H),3.92 (s, 2H), 4.07 (d, J=7.45 Hz, 2H), 7.03-7.10 (m, 2H), 7.13-7.27 (m,4H), 7.30-7.34 (m, 2H).

Example 1.224: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-4-methylphenyl)-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 242)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-(methylthio)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 2-fluoro-4-methylphenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.211. LCMSm/z=511.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.55 (m, 8H),1.73-1.82 (m, 1H), 1.88 (s, 3H), 2.08-2.18 (m, 1H), 2.36 (s, 3H), 2.48(t, J=7.58 Hz, 2H), 2.82 (t, J=7.20 Hz, 2H), 3.43 (d, J=7.07 Hz, 2H),3.95 (s, 2H), 4.08 (d, J=7.45 Hz, 2H), 7.03-7.11 (m, 2H), 7.15-7.27 (m,4H), 7.30-7.35 (m, 2H).

Example 1.225: Preparation of2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyi)methoxy)aceticAcid (Compound 243)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-(methylthio)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.211. LCMS m/z=509.7[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.56 (m, 8H), 1.74-1.82 (m,1H), 1.91 (s, 3H), 2.09-2.18 (m, 1H), 2.52 (t, J=8.46 Hz, 2H), 2.89 (t,J=8.21 Hz, 2H), 3.43 (d, J=6.95 Hz, 2H), 3.70 (s, 3H), 3.98 (s, 2H),4.06 (d, J=7.33 Hz, 2H), 6.74-6.80 (m, 2H), 6.87-6.92 (m, 1H), 7.17-7.36(m, 6H).

Example 1.226: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 244)

From tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-(methylthio)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.19 mmol) and2,3-difluorophenylboronic acid (30.0 mg, 0.19 mmol), the title compoundwas obtained using a similar method to the one described in Example1.211. LCMS m/z=515.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.58(m, 8H), 1.73-1.82 (m, 1H), 1.86 (s, 3H), 2.09-2.19 (m, 1H), 2.50 (t,J=7.20 Hz, 2H), 2.86 (t, J=7.20 Hz, 2H), 3.42 (d, J=7.07 Hz, 2H), 3.90(s, 2H), 4.09 (d, J=7.45 Hz, 2H), 7.13-7.20 (m, 1H), 7.20-7.34 (m, 6H),7.39-7.49 (m, 1H).

Example 1.227: Preparation of2-(((1s,4s)-4-((3-(2-Methoxyethyl)-5-(3-methoxyphenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 247)

From tert-butyl2-(((1s,4s)-4-((3-bromo-5-(2-methoxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-3-(2-methoxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.221. LCMS m/z=493.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06-1.20 (m, 4H), 1.22-1.37 (m,4H), 1.55-1.69 (m, 1H), 1.86-1.99 (m, 1H), 2.82 (t, J=7.39 Hz, 2H), 3.17(s, 3H), 3.21 (d, J=6.69 Hz, 2H), 3.51 (t, J=7.33 Hz, 2H), 3.68 (s, 3H),3.84 (s, 2H), 3.94 (d, J=7.45 Hz, 2H), 6.74-6.82 (m, 2H), 6.91-6.97 (m,1H), 7.06-7.34 (m, 6H).

Example 1.228: Preparation of2-(((1s,4s)-4-((5-(2-Methoxyethyl)-3-(3-methoxyphenyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 248)

From tert-butyl2-(((1s,4s)-4-((3-bromo-5-(2-methoxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((5-bromo-3-(2-methoxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.221. LCMS m/z=493.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.57 (m, 8H), 1.73-1.83 (m,1H), 2.05-2.19 (m, 1H), 2.83 (t, J=6.76 Hz, 2H), 3.13 (s, 3H), 3.34 (t,J=6.76 Hz, 2H), 3.43 (d, J=6.95 Hz, 2H), 3.55 (s, 3H), 3.93 (s, 2H),4.06 (d, J=7.45 Hz, 2H), 6.72-6.81 (m, 2H), 6.90-6.97 (m, 1H), 7.09-7.25(m, 3H), 7.29-7.42 (m, 3H).

Example 1.229: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-5-(2-(methylsulfonyl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 249)

To a solution of2-(((1s,4s)-4-((4-(3-chloro-2-fluorophenyl)-5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid (16.4 mg, 0.031 mmol) in DCM (2 mL) was added 3-chloroperbenzoicacid (16.0 mg, 0.093 mmol) was added. After stirred at room temperaturefor 30 min, the reaction mixture was concentrated and purified on prepHPLC to give the title compound as white solid (12.3 mg). LCMS m/z=563.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.58 (m, 8H), 1.73-1.84 (m,1H), 2.11-2.23 (m, 1H), 2.95 (s, 3H), 3.01 (t, J=8.02 Hz, 2H), 3.24 (t,J=8.02 Hz, 2H), 3.43 (d, J=6.95 Hz, 2H), 4.00 (s, 2H), 4.12 (d, J=7.33Hz, 2H), 7.21-7.32 (m, 6H), 7.32-7.39 (m, 1H), 7.58-7.65 (m, 1H).

Example 1.230: Preparation of2-(((1s,4s)-4-((3-(2-Cyanoethyl)-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 259) Step A: Preparation of3-(3-Phenyl-1H-pyrazol-5-yl)propanenitrile

To a solution of acetophenone (5.0 g, 41.6 mmol) in dry toluene (10 mL)was added LiHMDS (1.0 M in toluene) via syringe at 0° C. under argon.The reaction was allowed to stir at that temperature for 5 min and3-cyanopropanoyl chloride (4.89 g, 41.6 mmol) was added via syringe inone portion. The ice bath was removed and AcOH (glacial, 5 mL), EtOH(100 mL), and hydrazine hydrate (6.25 g, 125 mmol) were added. Themixture was brought to reflux for 16 h. After cooled to roomtemperature, the reaction was concentrated, extracted with EtOAc, driedover MgSO₄, and purified by column chromatography to give the titlecompound as yellowish oil (2.5 g). LCMS m/z=198.1 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.87 (t, J=4.42 Hz, 2H), 2.92 (t, J=4.04 Hz, 2H),6.59 (s, 1H), 7.25-7.48 (m, 3H), 7.63-7.81 (m, 2H), 13.06 (bs, 1H).

Step B: Preparation of3-(4-Bromo-3-phenyl-1H-pyrazol-5-yl)propanenitrile

To a solution of 3-(3-phenyl-1H-pyrazol-5-yl)propanenitrile (2.0 g,10.14 mmol) in methanol (20 mL) was added N-bromosuccinimide (1.80 g,10.14 mmol) in portions at room temperature. After stirred at roomtemperature for 16 h, the reaction was concentrated and extracted withEtOAc/H₂O, purified by column chromatography to give the title compoundas yellow oil (2.4 g). LCMS m/z=276.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 2.90 (t, J=4.80 Hz, 2H), 2.92 (t, J=4.29 Hz, 2H), 7.33-7.59 (m,3H), 7.76 (d, J=7.07 Hz, 2H), 13.45 (bs, 1H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

To a solution of 3-(4-bromo-3-phenyl-1H-pyrazol-5-yl)propanenitrile (2.0g, 7.24 mmol) in DMF (5 mL) were added cesium carbonate (1.16 g, 3.6mmol), followed by tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (2.36 g, 7.24mmol). The reaction was gently heated to 80° C. for 10 h. After cooledto room temperature, the reaction was quenched with water (2 mL),extracted with EtOAc, dried over MgSO₄, and purified by columnchromatography to give the title compound as clear oil (2.4 g) (mixtureof two isomers). LCMS m/z=516.2 [M+H]⁺.

Step D: Preparation of2-(((1s,4s)-4-((3-(2-Cyanoethyl)-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers (100 mg, 0.19 mmol) in dioxane (3 mL) wereadded phenylboronic acid (29.3 mg, 0.19 mmol),tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol), and K₂CO₃ (2M aq., 0.2 mL). The reaction was heated to 150° C. under microwaveirradiation for 4 h. After filtered and concentrated, the residue wastreated with HCl (4.0 M in dioxane, 5 mL) at room temperature for 10 h.The mixture was concentrated and purified by HPLC to give the titlecompound as white solid (13.5 mg).

LCMS m/z=458.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03-1.19 (m,4H), 1.22-1.36 (m, 4H), 1.55-1.66 (m, 1H), 1.88-1.99 (m, 1H), 2.79 (t,J=6.95 Hz, 2H), 2.93 (t, J=7.07 Hz, 2H), 3.20 (d, J=6.95 Hz, 2H), 3.91(s, 2H), 3.95 (d, J=7.45 Hz, 2H), 7.06-7.13 (m, 2H), 7.15-7.30 (m, 5H),7.36-7.45 (m, 3H).

Example 1.231: Preparation of2-(((1s,4s)-4-((5-(2-Cyanoethyl)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 260)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and phenylboronic acid, the title compound(one of the two regioisomers separated) was obtained using a similarmethod to the one described in Example 1.230. LCMS m/z=458.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.59 (m, 8H), 1.74-1.84 (m, 1H),2.06-2.18 (m, 1H), 2.58 (t, J=7.39 Hz, 2H), 2.97 (t, J=7.39 Hz, 2H),3.45 (d, J=7.07 Hz, 2H), 4.00 (s, 2H), 4.10 (d, J=7.45 Hz, 2H),7.19-7.27 (m, 5H), 7.28-7.32 (m, 2H), 7.34-7.44 (m, 3H).

Example 1.232: Preparation of2-(((1s,4s)-4-((3-(2-Cyanoethyl)-4-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 261)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.230. LCMS m/z=488.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05-1.20 (m, 4H), 1.22-1.36 (m,4H), 1.56-1.66 (m, 1H), 1.89-2.01 (m, 1H), 2.80 (t, J=7.20 Hz, 2H), 2.95(t, J=7.07 Hz, 2H), 3.21 (d, J=6.95 Hz, 2H), 3.60 (s, 3H), 3.91 (s, 2H),3.94 (d, J=7.45 Hz, 2H), 6.59-6.64 (m, 1H), 6.69 (d, J=7.71 Hz, 1H),6.75 (dd, J=8.02, 2.21 Hz, 1H), 7.17 (t, J=7.96 Hz, 1H), 7.23-7.30 (m,2H), 7.38-7.46 (m, 3H).

Example 1.233: Preparation of2-(((1s,4s)-4-((5-(2-Cyanoethyl)-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 262)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-methoxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.230. LCMS m/z=488.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.59 (m, 8H), 1.76-1.84 (m,1H), 2.08-2.18 (m, 1H), 2.61 (t, J=7.33 Hz, 2H), 2.99 (t, J=7.33 Hz,2H), 3.45 (d, J=7.20 Hz, 2H), 3.72 (s, 3H), 4.00 (s, 2H), 4.10 (d,J=7.45 Hz, 2H), 6.79 (s, 1H), 6.80 (d, J=1.64 Hz, 1H), 6.90-6.94 (m,1H), 7.19-7.27 (m, 3H), 7.28-7.37 (m, 3H).

Example 1.234: Preparation of2-(((1s,4s)-4-((5-(2-Cyanoethyl)-4-(3-hydroxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 263)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-hydroxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.230. LCMS m/z=474.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.59 (m, 8H), 1.73-1.84 (m,1H), 2.07-2.17 (m, 1H), 2.58 (t, J=7.39 Hz, 2H), 2.97 (t, J=7.39 Hz,2H), 3.45 (d, J=7.07 Hz, 2H), 4.00 (s, 2H), 4.09 (d, J=7.45 Hz, 2H),6.59-6.62 (m, 1H), 6.68 (d, J=7.58 Hz, 1H), 6.73-6.78 (m, 1H), 7.17-7.28(m, 5H), 7.31-7.37 (m, 1H).

Example 1.235: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 264)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.230. LCMS m/z=492.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.20 (m, 4H), 1.22-1.36 (m,4H), 1.55-1.66 (m, 1H), 1.90-2.01 (m, 1H), 2.82 (t, J=6.95 Hz, 2H), 2.95(t, J=6.95 Hz, 2H), 3.21 (d, J=6.95 Hz, 2H), 3.92 (s, 2H), 3.95 (d,J=7.45 Hz, 2H), 7.04-7.09 (m, 2H), 7.11-7.14 (m, 1H), 7.21-7.32 (m, 4H),7.40-7.47 (m, 2H).

Example 1.236: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 265)

From tert-butyl 2-(((Is,4s)-4-((4-bromo-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chlorophenylboronic acid, the titlecompound was obtained using a similar method to the one described inExample 1.230. LCMS m/z=492.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.32-1.60 (m, 8H), 1.76-1.84 (m, 1H), 2.09-2.18 (m, 1H), 2.63 (t, J=7.26Hz, 2H), 3.00 (t, J=7.33 Hz, 2H), 3.45 (d, J=7.07 Hz, 2H), 4.01 (s, 2H),4.10 (d, J=7.45 Hz, 2H), 7.19-7.33 (m, 7H), 7.40-7.44 (m, 2H).

Example 1.237: Preparation of2-(((1s,4s)-4-((3-(2-Cyanoethyl)-4-(3-fluorophenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 266)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.230. LCMS m/z=476.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.22 (m, 4H), 1.23-1.36 (m,4H), 1.57-1.67 (m, 1H), 1.91-2.00 (m, 1H), 2.82 (t, J=7.20 Hz, 2H), 2.97(t, J=7.07 Hz, 2H), 3.22 (d, J=6.82 Hz, 2H), 3.92 (s, 2H), 3.96 (d,J=7.58 Hz, 2H), 6.86-6.96 (m, 2H), 6.97-7.05 (m, 1H), 7.24-7.33 (m, 3H),7.40-7.46 (m, 3H).

Example 1.238: Preparation of2-(((1s,4s)-4-((5-(2-Cyanoethyl)-4-(3-fluorophenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 267)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-fluorophenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.230. LCMS m/z=476.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.61 (m, 8H), 1.75-1.86 (m,1H), 2.09-2.19 (m, 1H), 2.62 (t, J=7.33 Hz, 2H), 3.01 (t, J=7.33 Hz,2H), 3.46 (d, J=7.07 Hz, 2H), 4.01 (s, 2H), 4.11 (d. J=7.58 Hz, 2H),7.05-7.11 (m, 2H), 7.14-7.21 (m, 1H), 7.21-7.34 (m, 5H), 7.40-7.48 (m,1H).

Example 1.239: Preparation of2-(((1s,4s)-4-((3-(2-Cyanoethyl)-4-(3-hydroxyphenyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 268)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-hydroxyphenylboronic acid, the titlecompound (one of the two regioisomers separated) was obtained using asimilar method to the one described in Example 1.230. LCMS m/z=474.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03-1.19 (m, 4H), 1.20-1.36 (m,4H), 1.54-1.67 (m, 1H), 1.87-1.97 (m, 1H), 2.78 (t, J=7.01 Hz, 2H), 2.91(t, J=7.01 Hz, 2H), 3.20 (d, J=6.82 Hz, 2H), 3.91 (s, 2H), 3.93 (d,J=8.08 Hz, 2H), 6.46-6.54 (m, 2H), 6.59 (dd, J=8.15, 1.58 Hz, 1H), 7.04(t, J=7.83 Hz, 2H), 7.22-7.28 (m, 2H), 7.38-7.46 (m, 2H).

Example 1.240: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-)methyl)cyclohexyl)methoxy)aceticAcid (Compound 269)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chloro-2-fluorophenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.230. LCMSm/z=510.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.99-1.15 (m, 4H),1.16-1.34 (m, 4H), 1.55-1.67 (m, 1H), 1.81-1.93 (m, 1H), 2.82-2.94 (m,4H), 3.16 (d, J=6.95 Hz, 2H), 3.68 (s, 2H), 3.98 (d, J=7.45 Hz, 2H),7.39-7.46 (m, 3H), 7.48-7.60 (m, 5H).

Example 1.241: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 270)

From tert-butyl2-(((1s,4s)-4-((4-bromo-3-(2-cyanoethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-bromo-5-(2-cyanoethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a mixture of regioisomers and 3-chloro-2-fluorophenylboronic acid,the title compound (one of the two regioisomers separated) was obtainedusing a similar method to the one described in Example 1.230. LCMSm/z=510.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27-1.56 (m, 8H),1.71-1.83 (m, 1H), 2.00-2.11 (m, 1H), 2.83 (t, J=7.20 Hz, 2H), 3.11 (t,J=7.26 Hz, 2H), 3.41 (d, J=7.20 Hz, 2H), 3.81 (s, 2H), 4.11 (d, J=7.58Hz, 2H), 7.35-7.42 (m, 2H), 7.42-7.49 (m, 3H), 7.79-7.85 (m, 3H).

Example 1.242: Preparation of2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-5-(2-hydroxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 287) Step A: Preparation of Ethyl3-(2-Fluoro-4-methylphenyl)-3-oxo-2-phenylpropanoate

2-Fluoro-4-methylbenzoyl chloride was made 2 h before the reaction byadding oxalyl chloride (3.20 mL, 36.5 mmol) to a solution of2-fluoro-4-methylbenzoic acid (4.69 g, 30.5 mmol) in DCM (5 mL) at roomtemperature. After stirring for 2 h, the resulting solution wasconcentrated to dryness and dissolved in THF (10 mL), used as it waswithout further purification.

The solution of ethyl 2-phenylacetate (5 g, 30.5 mmol) in THF (20 mL)was cooled to −78° C. and LiHMDS (30.5 mL, 30.5 mmol) was added,followed by prior made solution of 2-fluoro-4-methylbenzoyl chloride inTHF (10 mL). The reaction was allowed to warm to room temperature slowlyand stirred for 4 h. Quenched with AcOH (2 mL), extracted with EtOAc,washed with brine, dried over MgSO₄, and purified by columnchromatography to give the title compound as clear liquid (7.10 g). LCMSm/z=301.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (t, J=7.07 Hz,3H), 2.32 (s, 3H), 4.22 (q, J=7.07 Hz, 2H), 5.77 (s, 1H), 7.03-7.17 (m,3H), 7.24-7.40 (m, 4H), 7.82 (t, J=8.21 Hz, 1H).

Step B: Preparation of 1-(2-Fluoro-4-methylphenyl)-2-phenylethanone

Ethyl 3-(2-fluoro-4-methylphenyl)-3-oxo-2-phenylpropanoate (8.0 g, 26.6mmol) was dissolved in THF (20 mL) and hydrogen chloride (37% wt., 32.0mL, 400 mmol) was added. The reaction was brought to reflux overnight.After cooled to room temperature, the reaction was diluted with H₂O (100mL) and neutralized to pH 8 with NaOH (4.0 M aq.). The mixture wasextracted with EtOAc (3×75 mL), dried over MgSO₄, and purified by columnchromatography to give the title compound as a clear oil (4.81 g). LCMSm/z=229.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.36 (s, 3H), 4.28 (s,2H), 7.11-7.18 (m, 2H), 7.19-7.26 (m, 3H), 7.27-7.34 (m, 2H), 7.77 (t,J=8.21 Hz, 1H).

Step C: Preparation of 1-(1H-Benzo[d][1,2,3]triazol-1-yl)but-3-en-1-one

Sulfurous dichloride (6.91 g, 58.1 mmol) was added to a stirred solutionof 1H-benzo[d][1,2,3]triazole (27.7 g, 232 mmol) in anhydrousdichloromethane (100 mL) at room temperature under argon atmosphere. Themixture was stirred for 30 min and but-3-enoic acid (5.0 g, 58.1 mmol)was added in one portion and stirring was continued for 2 h. Theresulting suspension was filtered off and washed with 2.0 M NaOH (3×50mL), dried over MgSO₄, and purified by column chromatography to give thetitle compound as white solid (5.12 g). LCMS m/z=188.1 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 4.24 (d, J=6.57 Hz, 2H), 5.28-5.42 (m, 2H),6.04-6.19 (m, 1H), 7.61 (t, J=7.71 Hz, 1H), 7.78 (t, J=7.71 Hz, 1H),8.24 (dd, J=10.61, 8.34 Hz, 2H).

Step D: Preparation of5-Allyl-3-(2-fluoro-4-methylphenyl)-4-phenyl-1H-pyrazole

To a solution of 1-(2-fluoro-4-methylphenyl)-2-phenylethanone (1.0 g,4.38 mmol) in THF (10 mL) was added LiHMDS (1.0 M in THF) (8.76 mL, 8.76mmol) slowly via syringe at 0° C. After stirring for 10 min,1-(1H-benzo[d][1,2,3]triazol-1-yl)but-3-en-1-one (0.984 g, 5.26 mmol)was added in one portion. The reaction was stirred at 0° C. for 30 minbefore quenched with AcOH (2 mL). To the reaction were added EtOH (30mL), hydrazine hydrate (0.658 g, 13.14 mmol), and heated to reflux for 1h. After cooled to room temperature, the reaction was concentrated andextracted with EtOAc/H₂O, washed with brine, dried over MgSO₄, andpurified by column chromatography to give the title compound as clearoil (0.50 g). LCMS m/z=293.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.31 (s, 3H), 3.40 (d, J=5.94 Hz, 2H), 4.94-5.08 (m, 2H), 5.88-6.00 (m,1H), 6.92-7.31 (m, 8H).

Step E: Preparation of2-(3-(2-Fluoro-4-methylphenyl)-4-phenyl-1H-pyrazol-5-yl)ethanol

5-Allyl-3-(2-fluoro-4-methylphenyl)-4-phenyl-1H-pyrazole (1.0 g, 3.42mmol) was dissolved in methanol (40 mL) and dichloromethane (10 mL) andcooled to −78° C. on a dry-ice/acetone bath. Ozone was bubbled throughthe solution for ˜2 h, until the solution appeared light blue. To thereaction added sodium borohydride (0.129 g, 3.42 mmol) slowly. Uponcomplete addition, the reaction was removed from the dry-ice bath andstirred at room temperature for 1 h. Excess solvent was removed underreduced pressure and the reaction was extracted with EtOAc/H₂O, driedover MgSO₄, and purified by column chromatography to give the titlecompound as clear oil (0.70 g). LCMS m/z=297.2 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.30 (s, 3H), 2.79 (t, J=7.20 Hz, 2H), 3.62 (t, J=7.33Hz, 2H), 6.93-7.00 (m, 1H), 7.09-7.14 (m, 2H), 7.15-7.23 (m, 3H),7.25-7.31 (m, 2H), 12.86 (bs, 1H).

Step F: Preparation of tert-Butyl2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-5-(2-hydroxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of2-(3-(2-fluoro-4-methylphenyl)-4-phenyl-1H-pyrazol-5-yl)ethanol (0.7 g,2.362 mmol) in DMF (10 mL) were added cesium carbonate (0.770 g, 2.362mmol) and tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (0.974 g, 2.362mmol). The reaction was gently heated to 60° C. for 2 h. After cooled toroom temperature, the reaction mixture was extracted with EtOAC/H₂O,dried over MgSO₄, and purified by column chromatography to give thetitle compound as a clear oil (0.75 g). LCMS m/z=537.5 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 1.14-1.29 (m, 4H), 1.33-1.46 (m, 4H), 1.47 (s,9H), 1.72-1.81 (m, 1H), 2.00-2.09 (m, 1H), 2.37 (s, 3H), 2.91 (t, J=5.56Hz, 2H), 3.30 (d, J=7.07 Hz, 2H), 3.89 (s, 2H), 3.90 (d, J=7.33 Hz, 2H),3.91 (t, J=5.81 Hz, 2H), 4.68 (s, 1H), 6.89-7.01 (m, 2H), 7.04-7.10 (m,1H), 7.13-7.27 (m, 5H).

Step G: Preparation of2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-5-(2-hydroxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 287)

tert-Butyl2-(((1s,4s)-4-((3-(2-fluoro-4-methylphenyl)-5-(2-hydroxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(0.50 g, 0.932 mmol) was dissolved in hydrogen chloride (4.0 M indioxane) (4.66 mL, 18.63 mmol) and stirred at room temperature for 16 h.The reaction was concentrated and purified by HPLC to give the titlecompound. LCMS m/z=481.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.07-1.19 (m, 4H), 1.21-1.41 (m, 4H), 1.55-1.72 (m, 1H), 1.86-1.97 (m,1H), 2.33 (s, 3H), 3.22 (d, J=6.82 Hz, 2H), 3.59 (t, J=5.81 Hz, 2H),3.82 (t, J=5.85 Hz, 2H), 3.91 (s, 2H), 3.93 (d, J=7.54 Hz, 2H), 4.55 (s,1H), 7.03-7.12 (m, 4H), 7.13-7.19 (m, 2H), 7.22-7.27 (m, 2H).

Example 1.243: Preparation of2-(((1s,4s)-4-((5-(2-fluoro-4-methylphenyl)-3-(2-hydroxyethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 285)

The title compound was obtained using a similar method to the onedescribed in Example 1.242. LCMS m/z=481.6 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) S ppm 1.32-1.53 (m, 8H), 1.71-1.81 (m, 1H), 2.08-2.17 (m, 1H),2.28 (s, 3H), 2.84 (t, J=7.07 Hz, 2H), 3.41 (d, J=7.07 Hz, 2H), 3.49 (t,J=7.20 Hz, 2H), 3.93 (s, 2H), 4.08 (d, J=7.58 Hz, 2H), 4.45 (s, 1H),6.86-6.98 (m, 1H), 7.08-7.13 (m, 2H), 7.16-7.31 (m, 5H).

Example 1.244: Preparation of2-(((1s,4s)-4-((5-(2-(Methylsulfonyl)ethyl)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 290) Step A: Preparation of1-(1H-benzo[d][1,2,3]triazol-1-yl)-3-(methylthio)propan-1-one

Sulfurous dichloride (4.95 g, 41.6 mmol) was added to a stirred solutionof 1H-benzo[d][1,2,3]triazole (19.83 g, 166 mmol) in anhydrousdichloromethane (300 mL) at room temperature under argon. The mixturewas stirred for 30 min and 3-(methylthio)propanoic acid (5.0 g, 41.6mmol) was added in one portion and stirring was continued for 2 h. Theresulting suspension was filtered off and the filtrated was washed with2 M NaOH (3×50 mL), dried over MgSO₄, and purified by columnchromatography to give the title compound as clear oil (5.12 g). LCMSm/z=222.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 2.21 (s, 3H), 3.05 (t,J=7.07 Hz, 2H), 3.74 (t, J=7.07 Hz, 2H), 7.42-7.54 (m, 1H), 7.56-7.69(m, 1H), 8.08 (d, J=8.34 Hz, 1H), 8.24 (d, J=8.08 Hz, 1H).

Step B: Preparation of5-(2-(Methylthio)ethyl)-4-phenyl-3-p-tolyl-1H-pyrazole

To a solution of 2-phenyl-1-p-tolylethanone (2.0 g, 9.51 mmol) in THF(10 mL) was added LiHMDS (1.0 M in THF) (19.02 mL, 19.02 mmol) slowlyvia syringe at 0° C. After stirring for 10 min,1-(1H-benzo[d][1,2,3]triazol-1-yl)-3-(methylthio)propan-1-one (2.53 g,11.41 mmol) was added in one portion. The reaction was stirred at 0° C.for 30 min before quenched with AcOH (2 mL). To the reaction were addedEtOH (30 mL), hydrazine hydrate (1.428 g, 28.5 mmol), and brought toreflux for 2 h. After cooled to room temperature, the reaction wasconcentrated and extracted with EtOAc/H₂O, washed with brine, dried overMgSO₄, and purified by column chromatography to give the title compounda as clear oil (1.50 g). LCMS m/z=309.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃)δ ppm 1.96 (s, 3H), 2.29 (s, 3H), 2.66 (t, J=7.71 Hz, 2H), 2.90 (t,J=7.58 Hz, 2H), 7.01-7.06 (m, 2H), 7.18-7.25 (m, 3H), 7.26-7.37 (m, 3H).

Step C: Preparation of tert-butyl2-(((1s,4s)-4-((5-(2-(Methylthio)ethyl)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 5-(2-(methylthio)ethyl)-4-phenyl-3-p-tolyl-1H-pyrazole(0.5 g, 1.621 mmol) in DMF (10 mL) were added cesium carbonate (0.528 g,1.621 mmol) and tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (0.669 g, 1.621mmol). The reaction was gently heated to 60° C. for 2 h. After cooled toroom temperature, the mixture was extracted with EtOAc/H₂O, dried overMgSO₄, and purified by column chromatography to give the title compoundas a clear oil. LCMS m/z=549.5 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm1.10-1.27 (m, 4H), 1.29-1.45 (m, 4H), 1.46 (s, 9H), 1.53-1.61 (m, 1H),1.73-1.81 (m, 1H), 2.04 (s, 3H), 2.35 (s, 3H), 2.73 (t, J=7.58 Hz, 2H),2.99 (t, J=7.58 Hz, 2H), 3.28 (d, J=6.82 Hz, 2H), 3.88 (s, 2H), 3.96 (d,J=7.58 Hz, 2H), 7.04-7.10 (m, 4H), 7.11-7.18 (m, 3H), 7.18-7.24 (m, 2H).

Step D: Preparation of2-(((1s,4s)-4-((5-(2-(Methylsulfonyl)ethyl)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 290)

tert-Butyl2-(((s,4s)-4-((5-(2-(methylthio)ethyl)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(0.50 g, 0.911 mmol) was dissolved in hydrogen chloride (4.0 M indioxane) (4.56 mL, 18.22 mmol) and stirred at room temperature for 16 h.The reaction was concentrated to dryness and dissolved indichloromethane (5 mL) and 3-chloroperoxybenzoic acid (0.550 g, 3.19mmol) was added. After stirred at room temperature for 1 h, the reactionwas concentrated and purified on HPLC. LCMS m/z=525.4 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.08-1.20 (m, 4H), 1.23-1.36 (m, 4H), 1.57-1.68(m, 1H), 1.90-2.00 (m, 1H), 2.32 (s, 3H), 2.97 (s, 3H), 3.04 (t, J=8.59Hz, 2H), 3.22 (d, J=6.82 Hz, 2H), 3.41 (t, J=8.08 Hz, 2H), 3.92 (d,J=7.38 Hz, 2H), 3.92 (s, 2H), 7.08-7.15 (m, 3H), 7.16-7.31 (m, 6H).

Example 1.245: Preparation of2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-5-(2-(methylsulfonyl)ethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 291) Step A: Preparation of3-(2-Fluoro-4-methylphenyl)-5-(2-(methylthio)ethyl)-4-phenyl-1H-pyrazole

To a solution of 1-(2-fluoro-4-methylphenyl)-2-phenylethanone (2.0 g,8.76 mmol) in THF (10 mL) was added LiHMDS (1.0 M in THF) (17.52 mL,17.52 mmol) slowly via syringe at 0° C. After stirring for 10 min,1-(1H-benzo[d][1,2,3]triazol-1-yl)-3-(methylthio)propan-1-one (2.327 g,10.51 mmol) was added in one portion. The reaction was stirred at 0° C.for 30 min before quenched with AcOH (2 mL). To the reaction were addedEtOH (30 mL), hydrazine hydrate (1.316 g, 26.3 mmol), and brought toreflux for 2 h. After cooled to room temperature, the reaction wasconcentrated and extracted with EtOAc/H₂O, washed with brine, dried overMgSO₄, and purified by column chromatography to give the title compoundas a clear oil (1.40 g). LCMS m/z=327.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃)δ ppm 1.94 (s, 3H), 2.22 (s, 3H), 2.65 (t, J=7.33 Hz, 2H), 2.88 (t,J=7.58 Hz, 2H), 6.71 (d, J=7.83 Hz, 1H), 6.80 (d, J=11.87 Hz, 1H), 6.97(t, J=7.96 Hz, 1H), 7.09-7.29 (m, 5H), 9.64 (bs, 1H).

Step B: Preparation of tert-Butyl2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-5-(2-(methylthio)ethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of3-(2-fluoro-4-methylphenyl)-5-(2-(methylthio)ethyl)-4-phenyl-1H-pyrazole(0.5 g, 1.532 mmol) in DMF (10 mL) were added cesium carbonate (0.499 g,1.532 mmol) and tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (0.632 g, 1.532mmol). The reaction was gently heated to 60° C. for 2 h. After cooled toroom temperature, the mixture was extracted with EtOAc/H₂O, dried overMgSO₄, and purified by column chromatography to give the title compoundas a clear oil. LCMS m/z=567.5 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm1.31-1.44 (m, 4H), 1.46 (s, 9H), 1.52-1.65 (m, 4H), 1.69-1.81 (m, 1H),1.84-1.92 (m, 1H), 2.04 (s, 3H), 2.35 (s, 3H), 2.55 (t, J=7.83 Hz, 2H),2.74 (t, J=7.58 Hz, 2H), 3.47 (d, J=7.07 Hz, 2H), 3.96 (s, 2H), 4.08 (d,J=7.33 Hz, 2H), 6.84-7.01 (m, 2H), 7.06-7.18 (m, 3H), 7.19-7.32 (m, 3H).

Step C: Preparation of2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-5-(2-(methylsulfonyl)ethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 291)

tert-Butyl2-(((1s,4s)-4-((3-(2-fluoro-4-methylphenyl)-5-(2-(methylthio)ethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(0.50 g, 0.882 mmol) was dissolved in hydrogen chloride (4.0 M indioxane) (4.41 mL, 17.64 mmol) and stirred at room temperature for 16 h.The reaction was concentrated and dissolved in DCM (5 mL).3-Chloroperoxybenzoic acid (0.533 g, 3.09 mmol) was added. After stirredat room temperature for 1 h, the reaction was concentrated and theresidue was purified by HPLC to give the title compound. LCMS m/z=543.4[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05-1.20 (m, 4H), 1.23-1.37 (m,4H), 1.57-1.69 (m, 1H), 1.89-1.99 (m, 1H), 2.34 (s, 3H), 2.97 (s, 3H),3.06 (t, J=8.21 Hz, 2H), 3.22 (d, J=6.82 Hz, 2H), 3.43 (t, J=8.21 Hz,2H), 3.92 (d, J=7.33 Hz, 2H), 3.91 (s, 2H), 7.05-7.14 (m, 3H), 7.15-7.23(m, 3H), 7.24-7.31 (m, 2H).

Example 1.246: Preparation of2-(((1s,4s)-4-((5-(2-Hydroxyethyl)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 292) Step A: Preparation of5-Allyl-4-phenyl-3-p-tolyl-1H-pyrazole

To a solution of 2-phenyl-1-p-tolylethanone (1.0 g, 4.76 mmol) in THF(10 mL) added LiHMDS (1.0 M in THF) (9.51 mL, 9.51 mmol) slowly viasyringe at 0° C. After stirring for 10 min,1-(1H-benzo[d][1,2,3]triazol-1-yl)but-3-en-1-one (1.068 g, 5.71 mmol)was added in one portion. The reaction was stirred at 0° C. for 30 minand then quenched with AcOH (2 mL). EtOH (30 mL) and hydrazine hydrate(0.714 g, 14.27 mmol) were added, and the reaction was heated to refluxfor 30 min. The reaction was cooled to room temperature, concentratedand the residue was extracted with EtOAc/H₂O, washed with brine, driedover MgSO₄, and purified by column chromatography to give the titlecompound as clear oil (0.47 g). LCMS m/z=275.0 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 2.31 (s, 3H), 3.38-3.43 (m, 2H), 5.07-5.14 (m, 2H),5.90-6.01 (m, 1H), 7.03-7.09 (m, 2H), 7.19-7.30 (m, 5H), 7.30-7.36 (m,2H).

Step B: Preparation of 2-(4-Phenyl-3-p-tolyl-1H-pyrazol-5-yl)ethanol

5-Allyl-4-phenyl-3-p-tolyl-1H-pyrazole (1.0 g, 3.64 mmol) was dissolvedin methanol (40 mL) and dichloromethane (10 mL) and cooled to −78° C. ona dry-ice/acetone bath. Ozone was bubbled through the solution for ˜2 h,until the solution appeared light blue. To the reaction was added sodiumborohydride (0.138 g, 3.64 mmol) and the reaction was removed from thedry-ice bath and stirred at room temperature for 1 h. Excess solvent wasremoved under reduced pressure and the reaction was extracted withEtOAc/H₂O, dried over MgSO₄, and purified by column chromatography togive the title compound as white solid (0.54 g). LCMS m/z=279.2 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H), 2.71 (t, J=7.33 Hz, 2H),3.57 (t, J=7.33 Hz, 2H), 4.65 (bs, 1H), 7.03-7.09 (m, 2H), 7.16-7.23 (m,3H), 7.24-7.31 (m, 2H), 7.32-7.40 (m, 2H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((5-(2-Hydroxyethyl)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 2-(4-phenyl-3-p-tolyl-1H-pyrazol-5-yl)ethanol (0.7 g,2.51 mmol) in DMF (10 mL) were added cesium carbonate (0.819 g, 2.51mmol) and tert-butyl 2-(((ls,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (1.037 g, 2.51 mmol).The reaction was gently heated to 60° C. for 2 h. The reaction wascooled to room temperature and extracted with EtOAc/H₂O. The organiclayer was dried over MgSO₄ and purified by column chromatography to givethe title compound as clear oil (0.75 g). LCMS m/z=519.5 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 1.34-1.45 (m, 4H), 1.49 (s, 9H), 1.55-1.63 (m,4H), 1.72-1.80 (m, 1H), 1.85-1.93 (m, 1H), 2.28 (s, 3H), 2.90 (t, J=6.95Hz, 2H), 3.47 (d, J=7.07 Hz, 2H), 3.66 (t, J=6.44 Hz, 2H), 3.96 (s, 2H),4.09 (d, J=7.58 Hz, 2H), 6.98-7.10 (m, 2H), 7.12-7.24 (m, 2H), 7.24-7.37(m, 5H).

Step D: Preparation of2-(((1s,4s)-4-((5-(2-Hydroxyethyl)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 292)

tert-Butyl2-(((1s,4s)-4-((5-(2-hydroxyethyl)-4-phenyl-3-p-tolyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(0.50 g, 0.964 mmol) was dissolved in hydrogen chloride (4.0 M indioxane) (4.82 mL, 19.28 mmol) and stirred at room temperature for 16 h.The reaction was concentrated and purified by HPLC to give the titlecompound. LCMS m/z=463.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.31-1.57 (m, 8H), 1.73-1.83 (m, 1H), 2.09-2.19 (m, 1H), 2.24 (s, 3H),2.75 (t, J=7.20 Hz, 2H), 3.44 (t, J=7.20 Hz, 2H), 3.44 (d, J=6.82 Hz,2H), 4.00 (s, 2H), 4.07 (d, J=7.33 Hz, 2H), 7.00-7.05 (m, 2H), 7.16-7.22(m, 4H), 7.27-7.40 (m, 3H).

Example 1.247: Preparation of2-(((1r,4r)-4-((5-(4-Fluorophenyl)-3-(methylthio)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 1) Step A: Preparation of3-(4-Fluorophenyl)-5-(methylthio)-4-phenyl-1H-pyrazole

To a solution of 1-(4-fluorophenyl)-2-phenylethanone (1.0 g, 4.67 mmol)in anhydrous THF (10 mL), was added a solution of 1.0 M KO-t-Bu in THF(2 mL). The reaction was stirred for 15 min at room temperature, andthen quenched with CS₂ (0.38 g, 5.04 mmol). After stirring for 30 min,iodomethane (1.45 g, 10.22 mmol) was added to the reaction over 5 min.The reaction was maintained at the same temperature for 4 h. Thereaction was poured into water and extracted with ethyl acetate. Theextract was dried over MgSO₄ and concentrated under reduced pressure togive a yellow solid (1.02 g). To the suspension of the above-mentionedyellow solid in ethanol (10 mL), hydrazine hydrate (0.70 g, 14.0 mmol)was added at room temperature. The reaction was refluxed for 4 h. Aftercooling to room temperature, the mixture was concentrated under reducedpressure and extracted with ethyl acetate. The organic extract was driedover MgSO₄ and concentrated under reduced pressure. The residue waspoured into 10% ethyl acetate in hexane and the precipitate was filteredand dried in air to give the title compound (0.69 g) as a white solid.LCMS m/z=285.4 [M+H]⁺.

Step B: Preparation of(2-(((1r,4r)-4-((5-(4-Fluorophenyl)-3-(methylthio)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of 3-(4-fluorophenyl)-5-(methylthio)-4-phenyl-1H-pyrazole(150 mg, 0.528 mmol) and tert-butyl2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (218 mg, 0.528mmol) in DMF (3 mL) was added sodium hydride (12.66 mg, 0.528 mmol) atroom temperature. The reaction was heated at 60° C. overnight. Aftercooling to room temperature, the reaction was poured into water andextracted with ethyl acetate. The organic extract was concentrated underreduced pressure and the resulting residue was purified by HPLC to givethe title compound (29 mg). LCMS m/z=469.8 [M+H]⁺.

Example 1.248: Preparation of2-(((1r,4r)-4-((3-(4-Fluorophenyl)-5-(methylthio)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 2)

From 3-(4-fluorophenyl)-5-(methylthio)-4-phenyl-1H-pyrazole andtert-butyl 2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, thetitle compound was obtained using a similar method to the one describedin Example 1.247, Step B. LCMS m/z=469.5 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.95 (m, 2H), 1.15 (m, 2H), 1.56 (m, 1H), 1.74 (m, 2H),181 (m, 2H), 1.89 (m, 1H), 2.10 (s, 3H), 3.25 (d, J=6.4 Hz, 2H), 3.89(s, 2H), 4.20 (d, J=7.2 Hz, 2H), 7.12-7.20 (m, 2H), 7.23-7.49 (m, 7H).

Example 1.249: Preparation of2-(((1r,4r)-4-((4-(3-Methoxyphenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aeeticAcid (Compound 6) Step A: Preparation of 3-Methyl-5-phenyl-1H-pyrazole

To a solution of 1-phenylbutane-1,3-dione (5.0 g, 30.8 mmol) in ethanol(50 mL), was added hydrazine hydrate (1.54 g, 30.8 mmol) at ambienttemperature. The reaction was refluxed for 5 h. After cooling, thereaction was concentrated under reduced pressure and extracted withethyl acetate. The extract was dried over MgSO₄ and concentrated underreduced pressure. The residue was added 10% ethyl acetate in hexane. Theprecipitate was filtered and washed with hexane. The white solid wasdried in air to give the title compound (3.9 g). LCMS m/z=159.3 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H), 6.65 (s, 1H), 7.34 (m,1H), 7.42 (m, 2H), 7.82 (m, 2H).

Step B: Preparation of 4-Iodo-3-methyl-5-phenyl-1H-pyrazole

To a solution of 5-methyl-3-phenyl-1H-pyrazole (1.5 g, 9.48 mmol) in THF(20 mL) and water (20 mL), were added sodium iodide (1.42 g, 9.48 mmol),iodine (3.61 g, 14.22 mmol), and K₂CO₃ (1.96 g, 14.22 mmol) at roomtemperature. The reaction was warmed to 100° C. and stirred for 10 h.After cooling to room temperature, the reaction was poured into waterand extracted with ethyl acetate, which was washed with 2.0 M aq. sodiumthiosulfite and saturated. NaHCO₃ successively. The extract was driedover MgSO₄ and concentrated under reduced pressure to give a semi-solid,which was recrystallized from 10% ethyl acetate in hexane to give thetitle compound (1.9 g). LCMS m/z=285.5 [M+H]⁺.

Step C: Preparation of tert-Butyl2-(((1r,4r)-4-((4-Iodo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1r,4r)-4-((4-Iodo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

To a solution of 4-iodo-5-methyl-3-phenyl-1H-pyrazole (1.0 g, 3.52 mmol)in DMF (10 mL), was added sodium hydride (0.084 g, 3.52 mmol) at ambienttemperature. After stirring for 10 min, a solution of tert-butyl2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (1.45 g, 3.52mmol) in DMF (1 mL) was added at room temperature. The reaction washeated to 45° C. and stirred for 8 h. After cooling to room temperature,the reaction was poured into H₂O and extracted with ethyl acetate, whichwas dried over MgSO₄ and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography togive the title compound (1.25 g) as a colorless oil. LCMS m/z=525.4[M+H]⁺.

Step D: Preparation of(2-(((1r,4r)-4-((4-(3-Methoxyphenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of regioisomers, tert-butyl2-(((1r,4r)-4-((4-iodo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4r)-4-((4-iodo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(200 mg, 0.381 mmol), in dioxane (2 mL), were added3-methoxyphenylboronic acid (58.0 mg, 0.381 mmol), Pd(PPh₃)₄(22.03 mg,0.019 mmol), and a 2.0 M aqueous solution of K₂CO₃ (105 mg, 0.763 mmol)at ambient temperature. The reaction was irradiated under microwave for1.5 h at 150° C. After cooling to room temperature, the reaction waspoured into water, extracted with ethyl acetate, and then dried overMgSO₄. The extract was concentrated under reduced pressure and theresidue was treated with 4.0 M HCl (5 mL) at room temperature. Afterstirring for 10 h, the reaction was concentrated under reduced pressureand purified by HPLC to give the title compound (25 mg). LCMS m/z=449.3[M+H]⁺.

Example 1.250: Preparation of2-(((1r,4r)-4-((4-(3-Methoxyphenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 7)

From a mixture of regioisomers, tert-butyl 2-(((Ir,4r)-4-((4-iodo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4r)-4-((4-iodo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,and 3-methoxyphenylboronic acid, the title compound was obtained using asimilar method to the one described in Example 1.250, Step D. 20 LCMSm/z=449.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.91 (m, 2H), 1.15 (m,2H), 1.59 (m, 1H), 1.75 (m, 2H), 1.82 (m, 2H), 1.95 (m, 1H), 2.25 (s,3H), 2.51 (s, 3H), 3.24 (d, J=6.8 Hz, 2H), 3.75 (s, 2H), 4.01 (d, J=7.4Hz, 2H), 6.65-6.89 (m, 3H), 7.26-7.49 (m, 6H).

Example 1.251: Preparation of2-(((1r,4r)-4-((5-Methyl-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 11)

To a solution of regioisomers, tert-butyl2-(((1r,4r)-4-((4-iodo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4r)-4-((4-iodo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(200 mg, 0.381 mmol), in dioxane (2 mL), were added phenylboronic acid(0.046 g, 0.381 mmol), Pd(PPh₃)₄(0.022 g, 0.019 mmol), and a 2.0 Maqueous solution of K₂CO₃ (0.105 g, 0.763 mmol) at ambient temperature.The reaction was irradiated under microwave for 4 h at 150° C. Aftercooling to room temperature, the reaction was poured into water,extracted with ethyl acetate, and then dried over MgSO₄. The extract wasconcentrated under reduced pressure and the residue was treated with 4.0M HCl (5 mL). After stirring for 10 h, the reaction was concentratedunder reduced pressure and purified by HPLC to give the title compound(0.104 g). LCMS m/z=419.3 [M+H]⁺.

Example 1.252: Preparation of2-(((1s,4s)-4-((5-(4-Fluorophenyl)-3-(methylthio)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 12)

To a solution of 3-(4-fluorophenyl)-5-(methylthio)-4-phenyl-1H-pyrazole(150.0 mg, 0.502 mmol) in DMF (5 mL), was added sodium hydride (12.66mg, 0.528 mmol) at room temperature. After stirring for 30 min, asolution of tert-butyl2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (218 mg, 0.528mmol) in DMF (1 mL) was added into the reaction at room temperature. Thereaction was heated at 60° C. overnight. After cooling to roomtemperature, the reaction was poured into water and extracted with ethylacetate. The extract was concentrated under reduced pressure and theresidue was treated with 4.0 M HCl in dioxane (5 mL). After standing for10 h, the reaction was concentrated under reduced pressure and purifiedby HPLC to give the title compound (21.0 mg). LCMS m/z=469.5 [M+H]⁺.

Example 1.253: Preparation of2-(((1s,4s)-4-((3-(4-Fluorophenyl)-5-(methylthio)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 10)

From 3-(4-fluorophenyl)-5-(methylthio)-4-phenyl-1H-pyrazole andtert-butyl 2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy), the titlecompound was obtained using a similar method to the one described inExample 1.252. LCMS m/z=496.4 [M+H]⁴.

Example 1.254: Preparation of2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 13) Step A: Preparation of tert-Butyl2-(((1r,4s)-4-((4-Iodo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1r,4s)-4-((4-Iodo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

To a solution of 4-iodo-5-methyl-3-phenyl-1H-pyrazole (1.0 g, 3.52 mmol)in DMF (5 mL), was added sodium hydride (0.084 g, 3.52 mmol) at roomtemperature. After stirring for 30 min, the reaction was treated withtert-butyl 2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(1.32 g, 0.528 mmol) in DMF (5 mL) at ambient temperature. The reactionwas stirred at 60° C. for 12 h. The reaction was poured into H₂O andextracted with ethyl acetate. The organic extract was dried over MgSO₄and concentrated under reduced pressure. The residue was purified bycolumn chromatography to give the titled compounds (1.2 g) as a mixtureof regioisomers. LCMS m/z=525.7 [M+H]⁺.

Step B: Preparation of(2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of regioisomers, tert-butyl2-(((1r,4s)-4-((4-iodo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4s)-4-((4-iodo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(0.2 g, 0.381 mmol), in dioxane (5 mL), were added3-methoxyphenylboronic acid (0.058 g, 0.381 mmol), Pd(PPh₃)₄(0.022 g,0.019 mmol), and a 2.0 M aqueous solution of K₂CO₃ (0.131 g, 0.952 mmol)at ambient temperature. The reaction was irradiated under microwave for4 h at 150° C. After cooling to room temperature, the mixture was pouredinto water and extracted with ethyl acetate. The extract wasconcentrated under reduced pressure and the residue was treated with 4.0M HCl in dioxane (5 mL). After standing for 10 h, the reaction wasconcentrated under reduced pressure and purified by HPLC to give thetitle compound (0.032 g). LCMS m/z=449.2 [M+H]⁺.

Example 1.255: Preparation of((1s,4s)-4-((5-Methyl-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methanolStep A: Preparation of(E)-1-Benzylidene-2-(((1s,4s)-4-(benzyloxymethyl)cyclohexyl)methyl)hydrazine

To a solution of tert-butyl2-(((1s,4s)-4-(benzyloxymethyl)cyclohexyl)methyl)hydrazinecarboxylate(1.0 g, 2.87 mmol) in dichloromethane (5 mL), was added TFA (5.0 mL) atroom temperature. After stirring for 3 h at the same temperature, themixture was concentrated under reduced pressure. The resulting residuewas dissolved in THF (10.0 mL) and benzaldehyde (0.31 g, 2.87 mmol) wasadded at room temperature. After stirring for 30 min, the reaction waspoured into water and extracted with ethyl acetate. The organic layerwas washed with sat.NaHCO₃, dried over MgSO₄, and concentrated underreduced pressure to give the titled compound (0.96 g) without furtherpurification. LCMS m/z=337.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.32-1.55 (m, 8H), 1.75-1.85 (m, 2H), 3.11 (m, 2H), 3.31 (d, J=2.5 Hz,2H), 4.45 (s, 2H), 7.21-7.54 (m, 1H).

Step B: Preparation of1-(((1s,4s)-4-(Benzyloxymethyl)cyclohexyl)methyl)-5-methyl-3,4-diphenyl-1H-pyrazole

To a solution of(E)-1-benzylidene-2-(((1s,4s)-4-(benzyloxymethyl)cyclohexyl)methyl)hydrazine(0.77 g, 2.28 mmol) and (E)-(2-nitroprop-1-enyl)benzene (0.37 g, 2.28mmol) in THF (5 mL) at −78° C., was added potassium butan-1-olate (0.25g, 2.28 mmol) dropwise. After stirring for 10 min, TFA (0.35 mL, 4.58mmol) was added at the same temperature and maintained for 2 h. Afterwarmed to room temperature, the reaction was poured into water andextracted with ethyl acetate. The organic layer was dried over MgSO₄,and concentrated under reduced pressure. The residue was purified bysilica gel to give the title compound (0.45 g). LCMS m/z=451.3 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) & ppm 1.29-1.52 (m, 8H), 1.75-1.80 (m, 1H),2.11-2.15 (m, 1H), 2.22 (s, 3H), 3.30 (s, 2H), 3.42 (d, J=2.5 Hz, 2H),4.14 (d, J=2.4 Hz, 2H), 7.23-7.42 (m, 15H).

Step C: Preparation of((1s,4s)-4-((5-Methyl-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methanol

To a solution of1-(((1s,4s)-4-(benzyloxymethyl)cyclohexyl)methyl)-5-methyl-3,4-diphenyl-1H-pyrazole(100 mg, 0.22 mmol) in MeOH (5 mL), was added ammonium formate (280 mg,4.44 mmol) followed by 10% Pd/C (5 mg). The reaction was heated to 80°C. for 10 h. The mixture was filtered. The filtrate was concentratedunder reduced pressure to give the titled compound (78 mg) as acolorless oil. LCMS m/z=361.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.34-1.55 (m, 8H), 1.56-1.60 (m, 1H), 2.10-2.15 (m, 1H), 2.21 (s, 3H),3.31 (d, J=2.5 Hz, 2H), 4.20 (d, J=2.4 Hz, 2H), 7.31-7.54 (m, 10H).

Example 1.256: Preparation of2-(((1s,4s)-4-((3-Methyl-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 15)

To a solution of regioisomers, tert-butyl2-(((1r,4s)-4-((4-iodo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4s)-4-((4-iodo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(0.2 g, 0.381 mmol), in dioxane (5 mL), were added phenylboronic acid(0.183 g, 1.5 mmol), Pd(PPh₃)₄(86.6 mg, 0.0075 mmol) and a 2.0 M aqueoussolution of K₂CO₃ (0.513 g, 3.5 mmol) at ambient temperature. Thereaction was irradiated under microwave for 1.5 h at 150° C. Aftercooling to room temperature, the reaction was poured into water andextracted with ethyl acetate. The organic extract was concentrated underreduced pressure and the residue was treated with 4.0 M HCl in dioxane(5 mL). After standing for 10 h, the reaction was concentrated underreduced pressure and purified by HPLC to give the title compound (0.075g). LCMS m/z=419.3 [M+H]⁺.

Example 1.257: Preparation of2-(((1s,4s)-4-((5-Methyl-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 16)

From a mixture of regioisomers, tert-butyl2-(((1r,4s)-4-((4-iodo-3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4s)-4-((4-iodo-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,and phenylboronic acid, the title compound was obtained using a similarmethod to the one described in Example 1.256. LCMS m/z=419.4 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.25-1.64 (m, 8H), 1.75 (m, 1H), 2.11 (m,1H), 2.20 (s, 3H), 3.45 (d, J=7.1 Hz, 2H), 4.05 (s, 2H), 4.12 (d, J=7.3Hz, 2H), 7.23-7.46 (m, 10H).

Example 1.258: Preparation of2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-3-(methylthio)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 30) Step A: Preparation of4-(3-Methoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazole

To a solution of 2-(3-methoxyphenyl)-1-phenylethanone (3.0 g, 13.26mmol) in anhydrous THF (10 mL), was added a solution of 1.0 M KO-t-Bu inTHF (13.26 mL, 13.26 mmol). The reaction was stirred for 15 min at roomtemperature, and carbon disulfide (1.01 g, 13.26 mmol) was added at 0°C. After 15 min, iodomethane (4.12 g, 29.0 mmol) was added dropwise andthe reaction was maintained at the same temperature for 4 h. Thereaction was poured into water and extracted with ethyl acetate. Theorganic extract was dried over MgSO₄ and concentrated under reducedpressure. The residue was suspended in ethanol (10 mL) and addedhydrazine hydrate (1.99 g, 39.8 mmol) at room temperature. The reactionwas refluxed for 4 h. After cooling to room temperature, the reactionwas concentrated under reduced pressure and extracted with ethylacetate. The organic extract was dried over MgSO₄ and concentrated underreduced pressure to give a semi-solid, which was recrystallized from 10%ethyl acetate in hexane to give the title compound (2.15 g). LCMSm/z=297.5 [M+H]⁺.

Step B: Preparation of(2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-3-(methylthio)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of 4-(3-methoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazole(100 mg, 0.337 mmol) in DMF (2 mL), was added sodium hydride (8.10 mg,0.337 mmol) at ambient temperature. After stirring for 10 min, asolution of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (139 mg, 0.337mmol) in DMF (1 mL) was added at room temperature. The reaction washeated to 45° C. and stirred for 8 h. After cooling to room temperature,the reaction was poured into H₂O and extracted with ethyl acetate, whichwas dried over MgSO₄ and concentrated under reduced pressure. Theresulting residue was treated with 4.0 M HCl in dioxane and stirred forovernight. The reaction was concentrated under reduced pressure and theresidue was purified by HPLC to give the title compound (21 mg). LCMSm/z=481.6 [M+H]⁺.

Example 1.259: Preparation of1-(((1s,4s)-4-(Benzyloxymethyl)cyclohexyl)methyl)-3-(4-fluorophenyl)-5-methyl-4-phenyl-1H-pyrazoleStep A: Preparation of(E)-1-(((1s,4s)-4-(benzyloxymethyl)cyclohexyl)methyl)-2-(4-fluorobenzylidene)hydrazine

To a solution of tert-butyl2-(((1s,4s)-4-(benzyloxymethyl)cyclohexyl)methyl)hydrazinecarboxylate(1.0 g, 2.87 mmol) in dichloromethane (5 mL), was added TFA (5.0 mL) atroom temperature. After stirring for 3 h at the same temperature, thereaction was concentrated under reduced pressure. The resulting residuewas dissolved in THF (10 mL) and 4-fluorobenzaldehyde (0.36 g, 2.87mmol) was added at room temperature. After stirring for 30 min, thereaction was poured into water and extracted with ethyl acetate. Theorganic layer was washed with saturated NaHCO₃, dried over MgSO₄, andthen concentrated under reduced pressure to give the title compound(0.96 g) without further purification.

LCMS m/z=355.3 [M+H]⁺.

Step B: Preparation of1-(((1s,4s)-4-(Benzyloxymethyl)cyclohexyl)methyl)-3-(4-fluorophenyl)-5-methyl-4-phenyl-1H-pyrazole

To a solution of(E)-1-(((1s,4s)-4-(benzyloxymethyl)cyclohexyl)methyl)-2-(4-fluorobenzylidene)hydrazine(0.97 g, 2.73 mmol) and (E)-(2-nitroprop-1-enyl)benzene (0.445 g, 2.73mmol) in THF (5 mL) at −78° C., was added potassium butan-1-olate (0.31g, 2.73 mmol) dropwise. After stirring for 10 min, TFA (0.42 mL, 5.45mmol) was added and the reaction maintained at −78° C. for 2 h. Afterwarmed to room temperature, the reaction was poured into water andextracted with ethyl acetate. The organic layer was dried over MgSO₄ andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography to give the title compound (0.2 g).LCMS m/z=469.3.

Example 1.260: Preparation of2-(((1s,4s)-4-((5-(4-Methoxyphenyl)-3-(methylthio)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 36) Step A: Preparation of3-(4-Methoxyphenyl)-5-(methylthio)-4-phenyl-1H-pyrazole

To a solution of 1-(4-methoxyphenyl)-2-phenylethanone (3.7 g, 16.35mmol) in anhydrous THF (10 mL), was added a solution of 1.0 M KO-t-Bu inTHF at ambient temperature. The reaction was stirred for 15 min at roomtemperature, then CS₂ (1.345 g, 17.66 mmol) was added. After 5 min,iodomethane (5.08 g, 35.8 mmol) was added and the reaction was stirredfor 4 h. The reaction was poured into water and extracted with ethylacetate. The extract was dried over MgSO₄ and concentrated under reducedpressure. The residue was dissolved in ethanol (10 mL) and addedhydrazine hydrate (2.45 g, 49.1 mmol) at room temperature. The reactionwas refluxed for 4 h. After cooling, the reaction was poured into waterand extracted with ethyl acetate. The organic layer was dried over MgSO₄and concentrated under reduced pressure. The residue was purified bycolumn chromatography to give the title compound (3.95 g) as a solid.LCMS m/z=297.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.41 (s, 3H),3.72 (s, 3H), 6.72-6.90 (m, 2H), 7.10-7.43 (m, 7H).

Step B: Preparation of(2-(((1s,4s)-4-((5-(4-Methoxyphenyl)-3-(methylthio)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of 3-(4-methoxyphenyl)-5-(methylthio)-4-phenyl-1H-pyrazole(100 mg, 0.337 mmol) in DMF (2 mL), was added sodium hydride (8.10 mg,0.337 mmol) at ambient temperature. After stirring for 10 min, asolution of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (139 mg, 0.337mmol) in DMF (1 mL) was added at room temperature. The reaction washeated to 45° C. and stirred for 8 h. After cooling to room temperature,the reaction was poured into H₂O and extracted with ethyl acetate, whichwas dried over MgSO₄ and concentrated under reduced pressure. Theresulting residue was treated with 4.0 M HCl in dioxane and stirred forovernight. The reaction was concentrated under reduced pressure and theresidue was purified by HPLC to give the title compound (31 mg). LCMSm/z=481.6 [M+H].

Example 1.261: Preparation of2-(((1s,4s)-4-((3-(4-Methoxyphenyl)-5-(methylthio)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 37)

From 3-(4-methoxyphenyl)-5-(methylthio)-4-phenyl-1H-pyrazole andtert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, thetitle compound was obtained using a similar method to the one describedin Example 1.260, Step B. LCMS m/z=481.5 [M+H]⁺.

Example 1.262: Preparation of2-(((1s,4s)-4-((3-(Methylthio)-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 75) Step A: Preparation of3,3-Bis(methylthio)-1,2-diphenylprop-2-en-1-one

To a solution of 1,2-diphenylethanone (5.0 g, 25.5 mmol) in anhydrousTHF (50 mL), was added a solution of 1.0 M KO-t-Bu in THF (51.0 mL, 51.0mmol). The reaction was stirred for 15 min at room temperature, and thenK₂CO₃ (2.095 g, 27.5 mmol) was added. After 10 min, iodomethane (7.92 g,55.8 mmol) was added and the reaction was stirred for 4 h. The reactionwas poured into water and extracted with ethyl acetate. The organiclayer was dried over MgSO₄ and concentrated under reduced pressure togive the title compound (6.9 g). LCMS m/z=301.3 [M+H]⁺.

Step B: Preparation of 5-(Methylthio)-3,4-diphenyl-1H-pyrazole

To a suspension of 3,3-bis(methylthio)-1,2-diphenylprop-2-en-1-one (2.5g, 8.32 mmol) in ethanol (20 mL), was added hydrazine hydrate (1.67 g,33.3 mmol) at room temperature. The reaction was refluxed for 6 h. Aftercooling, the reaction was poured into water and extracted with ethylacetate. The organic extract was dried over MgSO₄ and concentrated underreduced pressure.

The residue was purified by column chromatography to give the titlecompound (1.98 g). LCMS m/z=267.0 [M+H]⁺.

Step C: Preparation of(2-(((1s,4s)-4-((3-(Methylthio)-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of 5-(methylthio)-3,4-diphenyl-1H-pyrazole (100 mg, 0.375mmol) in DMF (3 mL), was added sodium hydride (9.01 mg, 0.375 mmol) atambient temperature. After stirring for 10 min, a solution of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (155 mg, 0.375mmol) in DMF (1 mL) was added at room temperature. The reaction washeated to 45° C. and stirred for 8 h. The reaction was poured into H₂Oand extracted with ethyl acetate, which was dried over MgSO₄ andconcentrated under reduced pressure. The resulting residue was treatedwith 4.0 M HCl in dioxane and stirred overnight. The reaction wasconcentrated under reduced pressure and purified by HPLC to give thetitle compound (19 mg). LCMS m/z=451.6 [M+H]⁺.

Example 1.263: Preparation of2-(((1s,4s)-4-((3-(2-Methoxyethylthio)-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 188) Step A: Preparation of5-(2-Methoxyethylthio)-3,4-diphenyl-1H-pyrazole

To a solution of 3,4-diphenyl-1H-pyrazole-5(4H)-thione (0.5 g, 1.981mmol) in DMF (5 mL), were added 1-bromo-2-methoxyethane (0.275 g, 1.981mmol) and K₂CO₃ (0.274 g, 1.981 mmol) at room temperature. Afterstirring for 4 h, the reaction was poured into water and extracted withethyl acetate. The organic extract was dried over MgSO₄ and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography to give the title compound (0.45 g). LCMS m/z=311.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.23 (s, 3H), 3.12-3.54 (m, 4H),7.22-7.49 (m, 10H), 13.2 (s, 1H).

Step B: Preparation of(2-(((1s,4s)-4-((3-(2-Methoxyethylthio)-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of 5-(2-methoxyethylthio)-3,4-diphenyl-1H-pyrazole (180mg, 0.580 mmol) in DMF (2 mL), was added sodium hydride (13.92 mg, 0.580mmol) in 0° C. After stirring for 10 min, tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (239 mg, 0.580mmol) was added and the reaction was warmed to 40° C. After stirring for12 h, the reaction was poured into water and extracted with ethylacetate. The organic extract was dried over MgSO₄ and concentrated underreduced pressure. The residue was treated with 4.0 M HCl in dioxane (5mL) and placed for 8 h. The mixture was concentrated under reducedpressure and purified by HPLC to give the title compound (32 mg). LCMSm/z=495.7 [M+H]⁺.

Example 1.264: Preparation of2-(((1s,4s)-4-((4-(2,5-Difluorophenyl)-3-(methylthio)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 77)

To a solution of regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(110 mg, 0.198 mmol), in dioxane (2 mL), were added2,5-difluorophenylboronic acid (31.2 mg, 0.198 mmol), Pd(PPh₃)₄(11.42mg, 9.88 μmol), and a 2.0 M aqueous solution of K₂CO₃ (54.6 mg, 0.395mmol) at ambient temperature. The reaction was irradiated undermicrowave for 1.5 h at 150° C. The reaction was filtered andconcentrated under reduced pressure. The residue was treated with 4.0 MHCl (5 mL). After stirring for 10 h, the reaction was concentrated underreduced pressure and purified by HPLC to give the title compound (19mg). LCMS m/z=487.4 [M+H]⁺.

Example 1.265: Preparation of2-(((1s,4s)-4-((4-(2,5-Difluorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 78)

From regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,and 2,5-difluorophenylboronic acid, the title compound was obtainedusing a similar method to the one described in Example 1.264. LCMSm/z=487.8 [M+H]⁺.

Example 1.266: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-3-(methylthio)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 82)

To a mixture of regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(110 mg, 0.198 mmol), in dioxane (2 mL), were added2,3-difluorophenylboronic acid (31.2 mg, 0.198 mmol), Pd(PPh₃)₄(11.42mg, 9.88 μmol), and a 2.0 M aqueous solution of K₂CO₃ (54.6 mg, 0.395mmol) at ambient temperature. The reaction was irradiated undermicrowave for 1.5 h at 150° C. After cooling to room temperature, thereaction was poured into water and extracted with ethyl acetate. Theorganic extract was concentrated under reduced pressure and theresulting residue was treated with 4.0 M HCl in dioxane (5 mL). Afterstanding for 10 h, the reaction was concentrated under reduced pressureand purified by HPLC to give the title compound (13 mg). LCMS m/z=487.4[M+H]⁺.

Example 1.267: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 83)

From a mixture of regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4r)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,and 2,3-difluorophenylboronic acid, the title compound was obtainedusing a similar method to the one described in Example 1.266. LCMSm/z=487.4 [M+H]⁺.

Example 1.268: Preparation of2-(((1s,4s)-4-((4-(3-Isopropoxyphenyl)-3-(methylthio)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 84)

To a mixture of regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(110 mg, 0.198 mmol, 1:3 mixture), in dioxane (2 mL), were added3-isopropoxyphenylboronic acid (35.6 mg, 0.198 mmol), Ph(PPh₃)₄ (11.42mg, 9.88 μmol), and a 2.0 M aqueous solution of K₂CO₃ (54.6 mg, 0.395mmol) at ambient temperature. The reaction was irradiated undermicrowave for 1.5 h at 150° C. After cooling to room temperature, thereaction was poured into water and extracted with ethyl acetate. Theextract was concentrated under reduced pressure and the resultingresidue was treated with 4.0 M HCl in dioxane (5 mL). After standing for10 h, the reaction was concentrated under reduced pressure and purifiedby HPLC to give the title compound (21 mg). LCMS m/z=509.5 [M+H]⁺.

Example 1.269: Preparation of2-(((1s,4s)-4-((4-(3-Isopropoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 85)

From a mixture of regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4r)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,and 3-isopropoxyphenylboronic acid, the title compound was obtainedusing a similar method to the one described in Example 1.268. LCMSm/z=509.8 [M+H]⁺.

Example 1.270: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-5-(methylsulfonyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 86)

To a solution of2-(((1s,4s)-4-((4-(2,3-difluorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid (10 mg, 0.021 mmol) in CH₂C₂(2 mL), was added mCPBA (3.55 mg, 0.021mmol) at room temperature. The reaction was stirred for 3 h at roomtemperature. The reaction was poured into water and extracted with ethylacetate. The extract was dried over MgSO₄ and concentrated under reducedpressure. The resulting residue was purified by HPLC to give the titlecompound (9 mg). LCMS m/z=519.7 [M+H]⁺.

Example 1.271: Preparation of2-(((1s,4s)-4-((4-(2,5-Difluorophenyl)-5-(methylsulfonyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 87)

To a solution of2-(((1s,4s)-4-((4-(2,5-difluorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid (10 mg, 0.021 mmol) in CH₂Cl₂ (2 mL), was added mCPBA (7.09 mg,0.041 mmol) at room temperature. The reaction was stirred for 3 h atroom temperature. The reaction was poured into water and extracted withethyl acetate. The extract was dried over MgSO₄ and concentrated underreduced pressure. The resulting residue was purified by HPLC to give thetitle compound (8 mg). LCMS m/z=519.7 [M+H]⁺.

Example 1.272: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 91)

To a mixture of regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.270 mmol), in dioxane (1 mL), were added3-fluorophenylboronic acid (37.7 mg, 0.270 mmol), Pd(PPh₃)₄(1.56 mg,1.348 μmol) and a 2.0 M aqueous solution of K₂CO₃ (0.270 mL, 0.539 mmol)at ambient temperature. The reaction was heated under microwave at 120°C. for 1.5 h. The reaction was poured into water and extracted withethyl acetate. The organic extract was dried over MgSO₄ and concentratedunder reduced pressure. The resulting residue was treated with hydrogenchloride (3.37 mL, 13.48 mmol) and stirred for 5 h. The mixture wasconcentrated under reduced pressure and purified by HPLC to give thetitle compound (93 mg). LCMS m/z=469.3 [M+H]⁺.

Example 1.273: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-3-methoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 92)

To a mixture of regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.270 mmol), in dioxane (I mL), were added2-fluoro-3-methoxyphenylboronic acid (45.8 mg, 0.270 mmol),Pd(PPh₃)₄(1.557 mg, 1.348 μmol) and a 2.0 M aqueous solution of K₂CO₃(0.270 mL, 0.539 mmol) at ambient temperature. The reaction was heatedunder microwave at 120° C. for 1.5 h. The reaction was poured into waterand extracted with ethyl acetate. The organic extract was dried overMgSO₄ and concentrated under reduced pressure. The resulting residue wastreated with hydrogen chloride (3.37 mL, 13.48 mmol) and stirred for 5h. The reaction was concentrated under reduced pressure and purified byHPLC to give the title compound (102 mg). LCMS m/z=499.1 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆)S ppm 1.34-1.61 (m, 8H), 1.85 (m, 1H), 2.11 (s, 3H),2.21 (m, 1H), 3.52 (d, J=7.1 Hz, 2H), 3.83 (s, 3H), 3.92 (s, 2H), 4.28(d, J=7.4 Hz, 2H), 6.80-6.91 (m, 2H), 7.23-7.42 (m, 6H).

Example 1.274: Preparation of2-(((1s,4s)-4-((4-(4-Fluorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 94)

To a mixture of regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.270 mmol), in dioxane (1 mL), was added 4-fluorophenylboronicacid (37.7 mg, 0.270 mmol), Pd(PPh₃)₄(15.57 mg, 0.013 mmol) and a 2.0 Maqueous solution of K₂CO₃ (74.5 mg, 0.539 mmol) at ambient temperature.The reaction was heated under microwave at 120° C. for 1.5 h. Thereaction was poured into water and extracted with ethyl acetate. Theextract was dried over MgSO₄ and concentrated under reduced pressure.The resulting residue was treated with hydrogen chloride (3.37 mL, 13.48mmol) and stirred for 5 h. The reaction was concentrated under reducedpressure and purified by HPLC to give the title compound (96 mg). LCMSm/z=469.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.35 (m, 8H) 1.63(m, 1H), 1.95 (s, 3H), 2.09 (m, 1H), 3.48 (d, J=7.0 Hz, 2H), 3.79 (s,2H), 4.10 (d, J=7.2 Hz, 2H), 6.94-7.09 (m, 9H).

Example 1.275: Preparation of2-(((1s,4s)-4-((5-(Methylthio)-3-phenyl-4-(3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 96)

To a mixture of regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.270 mmol), in dioxane (1 mL), was added3-(trifluoromethyl)phenylboronic acid (51.2 mg, 0.270 mmol),Pd(PPh₃)₄(15.57 mg, 0.013 mmol) and a 2.0 M aqueous solution of K₂CO₃(74.5 mg, 0.539 mmol) at ambient temperature. The reaction was heatedunder microwave at 120° C. for 1.5 h. The reaction was poured into waterand extracted with ethyl acetate. The extract was dried over MgSO₄ andconcentrated under reduced pressure. The resulting residue was treatedwith hydrogen chloride (3.37 mL, 13.48 mmol) and stirred for 5 h. Thereaction was concentrated under reduced pressure and purified by HPLC togive the title compound (85 mg). LCMS m/z=519.7[M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.38-1.59 (m, 8H), 1.85 (m, 1H), 2.10 (s, 3H), 2.25 (m,1H), 3.52 (d, J=7.0 Hz, 2H), 4.01 (s, 2H), 4.31 (d, J=7.2 Hz, 2H),7.29-7.65 (m, 9H).

Example 1.276: Preparation of2-(((1s,4s)-4-((4-(4-Chlorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 97)

To a mixture of regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.270 mmol), in dioxane (1 mL), was added 4-chlorophenylboronicacid (42.1 mg, 0.270 mmol), Pd(PPh₃)₄(15.57 mg, 0.013 mmol) and a 2.0 Maqueous solution of K₂CO₃ (74.5 mg, 0.539 mmol) at ambient temperature.The reaction was heated under microwave at 120° C. for 1.5 h. Thereaction was poured into water and extracted with ethyl acetate. Theextract was dried over MgSO₄ and concentrated under reduced pressure.The resulting residue was treated with hydrogen chloride (3.37 mL, 13.48mmol) and was stirred for 5 h. The reaction was concentrated underreduced pressure and purified by HPLC to give the title compound (98mg). LCMS m/z=485.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) ppm 1.21-1.45 (m,8H), 1.68 (m, 1H), 1.99 (s, 3H), 2.10 (m, 1H), 3.35 (d, J=7.1 Hz, 2H),3.87 (s, 2H), 4.15 (d, J=7.2 Hz, 2H), 7.12-7.38 (m, 9H).

Example 1.277: Preparation of2-(((1s,4s)-4-((5-(Methylthio)-3-phenyl-4-(thiophen-2-yl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 108)

To a mixture of regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.270 mmol), in dioxane (1 mL), was added thiophen-2-ylboronicacid (34.5 mg, 0.270 mmol), Pd(PPh₃)₄(15.57 mg, 0.013 mmol) and a 2.0 Maqueous solution of K₂CO₃ (74.5 mg, 0.539 mmol) at ambient temperature.The reaction was heated under microwave at 120° C. for 1.5 h. Thereaction was poured into water and extracted with ethyl acetate. Theextract was dried over MgSO₄ and concentrated under reduced pressure.The resulting residue was treated with hydrogen chloride (3.37 mL, 13.48mmol) and was stirred for 5 h. The reaction was concentrated underreduced pressure and purified by HPLC to give the title compound (89mg). LCMS m/z=457.1 [M+H]⁺.

Example 1.278: Preparation of2-(((1s,4s)-4-((5-(Methylthio)-3-phenyl-4-(thiophen-3-yl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 110)

To a mixture of regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl 2-(((ls,4s)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.270 mmol), in dioxane (1 mL), was added thiophen-3-ylboronicacid (34.5 mg, 0.270 mmol), Pd(PPh₃)₄(15.57 mg, 0.013 mmol) and a 2.0 Maqueous solution of K₂CO₃ (74.5 mg, 0.539 mmol) at ambient temperature.The reaction was heated under microwave at 120° C. for 1.5 h. Thereaction was poured into water and extracted with ethyl acetate. Theorganic extract was dried over MgSO₄ and concentrated under reducedpressure. The resulting residue was treated with hydrogen chloride (3.37mL, 13.48 mmol) and stirred for 5 h. The mixture was concentrated underreduced pressure and purified by HPLC to give the title compound (106mg). LCMS m/z=457.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.61(m, 8H), 1.86 (m, 1H), 1.99 (m, 1H), 2.22 (s, 3H), 3.61 (d, J=7.1 Hz,2H), 3.99 (s, 2H), 4.24 (d, J=7.4 Hz, 2H), 7.01-7.69 (m, 8H).

Example 1.279: Preparation of2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-5-(methylsulfinyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 114)

To a solution of2-(((1s,4s)-4-((4-(3-methoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid (52 mg, 0.108 mmol) in DCM (1 mL), was added mCPBA (18.67 mg, 0.108mmol) portionwise at room temperature. After stirring for 30 min, thereaction was poured into water and extracted with ethyl acetate. Theextract was dried over MgSO₄ and concentrated under reduced pressure.The resulting residue was purified by HPLC to provide the title compound(40 mg). LCMS m/z=497.2 [M+H]⁺.

Example 1.280: Preparation of2-(((1s,4s)-4-((4-(3-Fluoro-5-methylphenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 134)

To a mixture of regioisomers, tert-butyl2-(((1s,4s)-4-((4-iodo-3-methylthio-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1s,4s)-4-((4-iodo-5-methylthio-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(500 mg, 0.898 mmol), in dioxane (5 mL), was added3-fluoro-5-methylphenylboronic acid (138 mg, 0.898 mmol), Pd(PPh₃)₄(51.9mg, 0.045 mmol) and a 2.0 M aqueous solution of K₂CO₃(248 mg, 1.797mmol) at ambient temperature. The reaction was heated under Microwave at120° C. for 1.5 h. The reaction was poured into water and extracted withethyl acetate. The extract was dried over MgSO₄ and concentrated underreduced pressure. The resulting residue was treated with 4.0 M hydrogenchloride (11.23 mL, 44.9 mmol) in dioxane and stirred for 5 h. Thereaction was concentrated under reduced pressure and purified by HPLC.The lyophilized solid was dissolved in acetonitrile (1 mL) and H₂O (2mL) and added NaOH (14.6 mg, 0.367 mmol) in H₂O (1 mL). The mixture wasdried under reduced pressure to give the title compound (185 mg). LCMSm/z=483.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.65 (m, 8H),1.76 (m, 1H), 2.18 (s, 3H), 2.21 (m, 1H), 2.35 (s, 3H), 3.45 (d, J=7.2Hz, 2H), 3.98 (s, 2H), 4.28 (d, J=7.4 Hz, 2H), 6.85-7.08 (m, 3H),7.21-7.35 (m, 5H).

Example 1.281: Preparation of2-(((1r,4s)-4-((3-((S)-3,4-Dihydroxybutyl)-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 156) Step A: Preparation of(R)-4-(3-phenyl-1H-pyrazol-5-yl)butane-1,2-diol

To a solution of 5-(but-3-enyl)-3-phenyl-1H-pyrazole (3.0 g, 15.13 mmol)in isopropanol (20 mL) and H₂O (20 mL), was added AD-mix-a (20.0 g) atroom temperature. The reaction was stirred for 48 h at room temperature.The reaction was poured into saturated Na₂SO₃ (20 mL) and extracted withethyl acetate The extract was dried over MgSO₄ and concentrated underreduced pressure to give the title compound (2.45 g) as an oil, whichwas used without further purification.

LCMS m/z=232.9 [M+H]⁺.

Step B: Preparation of(R)-5-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazole

To a solution of (R)-4-(3-phenyl-1H-pyrazol-5-yl)butane-1,2-diol (2.5 g,10.76 mmol) in acetone (50 mL), were added 2,2-dimethoxypropane (11.21g, 108 mmol) and PTSA (0.185 g, 1.076 mmol) at room temperature. Afterstirring for 3 h, the reaction was concentrated under reduced pressure.The resulting residue was poured into water and extracted with ethylacetate. The extract was dried over MgSO₄ and concentrated under reducedpressure to give the title compound without further purification. LCMSm/z=273.4 [M+H]⁺.

Step C: Preparation of(R)-4-bromo-5-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazole

To a solution of(R)-5-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazole(2.3 g, 8.45 mmol) and MP-carbonate (26 g, 84.5 mmol) in CH₂Cl₂ (100mL), was added bromine (1.350 g, 8.45 mmol) dropwise at 0° C. Afterstirring for 1 h, MP-carbonate was filtered off and washed with CH₂Cl₂.The combined organic layer was poured into water, extracted with CH₂Cl₂,dried over MgSO₄, and then concentrated under reduced pressure. Theresulting residue was purified by column chromatography to give thetitle compound (2.81 g) as an oil. LCMS m/z=351.2 [M+H]⁺.

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-5-(2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-Butyl2-(((1s,4s)-4-((4-Bromo-3-(2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateas a Mixture of Regioisomers

To a solution of(R)-4-bromo-5-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazole(1.23 g, 3.50 mmol) in DMF (10 mL), was sodium hydride (0.084 g, 3.50mmol) added at ambient temperature. After stirring for 30 min,(R)-tert-butyl2-((4-((4-bromo-3-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(1.45 g, 3.50 mmol) was added and the reaction was heated to 45° C.After stirring for 12 h, the reaction was poured into H₂O and extractedwith ethyl acetate, which was dried over MgSO₄ and concentrated underreduced pressure. The resulting residue was purified by columnchromatography to give the title compounds (1.82 g, 1:3 ratio) as amixture of regioisomers. LCMS m/z=591.7 [M+H]⁺.

Step E: Preparation of(2-(((1r,4s)-4-((3-((S)-3,4-dihydroxybutyl)-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of regioisomers, tert-butyl2-(((1r,4s)-4-((4-bromo-3-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4s)-4-((4-bromo-5-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.254 mmol), in dioxane (1 mL), were added phenylboronic acid(30.9 mg, 0.254 mmol), Pd(PPh₃)₄(14.65 mg, 0.013 mmol) and a 2.0 Maqueous solution of K₂CO₃ (70.1 mg, 0.507 mmol) at ambient temperature.The reaction was heated under microwave at 120° C. for 1.5 h. Aftercooling to room temperature, the reaction was poured into water andextracted with ethyl acetate. The organic extract was dried over MgSO₄and concentrated under reduced pressure. The residue was treated with4.0 M HCl in dioxane (5 mL). After standing for 10 h, the reaction wasconcentrated under reduced pressure and purified by HPLC to give thetitle compound (12 mg). LCMS m/z=493.5 [M+H]+

Example 1.282: Preparation of2-(((1r,4s)-4-((5-((S)-3,4-Dihydroxybutyl)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 157)

From a mixture of regioisomers, tert-butyl2-(((1r,4s)-4-((4-bromo-3-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4s)-4-((4-bromo-5-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,and phenylboronic acid, the title compound was obtained by using asimilar method to the one described in Example 1.281. LCMS m/z=493.7[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.78 (m, 10H), 1.86 (m,1H), 2.10 (s, 1H), 2.63 (m, 1H), 2.71 (m, 1H), 3.10 (m, 2H), 3.12-3.22(m, 1H), 3.35 (d, J=7.2 Hz, 2H), 3.95 (s, 2H), 4.02 (d, J=7.3 Hz, 2H),7.02-7.35 (m, 10H).

Example 1.283: Preparation of2-(((1r,4s)-4-((5-((S)-3,4-Dihydroxybutyl)-4-(3-fluorophenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 158)

To a solution of regioisomers, tert-butyl2-(((1r,4s)-4-((4-bromo-3-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4s)-4-((4-bromo-5-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.254 mmol), in dioxane (1 mL), were added3-fluorophenylboronic acid (35.5 mg, 0.254 mmol), Pd(PPh₃)₄(14.65 mg,0.013 mmol) and a 2.0 M aqueous solution of K₂CO₃ (70.1 mg, 0.507 mmol)at ambient temperature. The reaction was heated under microwave at 120°C. for 1.5 h. The reaction was poured into water and extracted withethyl acetate. The extract was dried over MgSO₄ and concentrated underreduced pressure. The residue was treated with 4.0 M HCl in dioxane.After stirring for 5 h, the reaction was concentrated under reducedpressure and purified by HPLC to give the title compound (45 mg). LCMSm/z=511.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10-1.77 (m, 10H),1.78 (m, 1H), 1.98 (m, 1H), 2.72 (m, 1H), 2.80 (m, 1H), 3.20-3.40 (m,3H), 3.38 (d, J=7.2 Hz, 2H), 3.97 (s, 2H), 3.99 (d, J=7.3 Hz, 2H),7.15-7.38 (m, 9H).

Example 1.284: Preparation of2-(((1r,4s)-4-((4-(3,4-Difluorophenyl)-3-((S)-3,4-dihydroxybutyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 159)

To a solution of regioisomers, tert-butyl2-(((1r,4s)-4-((4-bromo-3-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4s)-4-((4-bromo-5-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.254 mmol), in dioxane (I mL), were added3,4-difluorophenylboronic acid (40.0 mg, 0.254 mmol), Pd(PPh₃)₄(14.65mg, 0.013 mmol) and a 2.0 M aqueous solution of K₂CO₃ (70.1 mg, 0.507mmol) at ambient temperature. The reaction was heated under microwave at120° C. for 1.5 h. After cooling to room temperature, the reaction waspoured into water and extracted with ethyl acetate. The extract wasconcentrated under reduced pressure and the resulting residue wastreated with 4.0 M HCl in dioxane (5 mL). After standing for 10 h, thereaction was concentrated under reduced pressure and purified by HPLC togive the title compound (12 mg). LCMS m/z=529.7 [M+H]⁺.

Example 1.285: Preparation of2-(((1r,4s)-4-((4-(3,4-Difluorophenyl)-5-((S)-3,4-dihydroxybutyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 160)

From regioisomers, tert-butyl2-(((1r,4s)-4-((4-bromo-3-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4s)-4-((4-bromo-5-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate,and 3,4-difluorophenylboronic acid, the title compound was obtained byusing similar method to the one described in Example 1.284. LCMSm/z=529.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10-1.77 (m, 10OH),1.75 (m, 1H), 2.10 (m, 1H), 2.70 (m, 1H), 2.75 (m, 1H), 3.15 (m, 1H),3.21 (m, 1H), 3.32 (m, 1H), 3.35 (d, J=7.2 Hz, 2H), 3.97 (s, 2H), 3.98(d, J=7.2 Hz, 2H), 6.95 (m, 1H), 7.14-7.41 (m, 7H).

Example 1.286: Preparation of2-(((1r,4s)-4-((4-(3-Chlorophenyl)-5-((S)-3,4-dihydroxybutyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 162)

To a solution of regioisomers, tert-butyl2-(((1r,4s)-4-((4-bromo-3-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4s)-4-((4-bromo-5-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.254 mmol), in dioxane (1 mL), were added3-chlorophenylboronic acid (39.7 mg, 0.254 mmol), Pd(PPh₃)₄(14.65 mg,0.013 mmol) and a 2.0 M aqueous solution of K₂CO₃ (70.1 mg, 0.507 mmol)at ambient temperature. The reaction was heated under microwave at 120°C. for 1.5 h. The reaction was poured into water and extracted withethyl acetate. The extract was dried over MgSO₄ and concentrated underreduced pressure. The residue was treated with 4.0 M HCl in dioxane (5mL). After stirring for 5 h, the reaction was concentrated under reducedpressure and purified by HPLC to give the title compound (65 mg). LCMSm/z=528.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.65 (m, 10H),1.80 (m, 1H), 2.12 (m, 1H), 2.72 (m, 1H), 2.80 (m, 1H), 3.20 (m, 1H),3.25 (m, 1H), 3.42 (m, 1H), 3.45 (d, J=7.2 Hz, 2H), 4.00 (s, 2H), 4.05(d, J=7.2 Hz, 2H), 7.13-7.42 (m, 9H).

Example 1.287: Preparation of2-(((1s,4s)-4-((5-((R)-3,4-Dihydroxybutyl)-4-(3-fluorophenyl)-3-phenyl-H1-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 169)

To a solution of regioisomers, tert-butyl2-(((1r,4s)-4-((4-bromo-3-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4s)-4-((4-bromo-5-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.254 mmol), in dioxane (1 mL), were added3-fluorophenylboronic acid (35.5 mg, 0.254 mmol), Pd(PPh₃)₄(14.65 mg,0.013 mmol) and a 2.0 M aqueous solution of K₂CO₃ (70.1 mg, 0.507 mmol)at ambient temperature. The reaction was heated under microwave at 120°C. for 1.5 h. The reaction was poured into water and extracted withethyl acetate. The organic extract was dried over MgSO₄ and concentratedunder reduced pressure. The residue was treated with 4.0 M HCl indioxane (5 mL). After stirring for 5 h, the reaction was concentratedunder reduced pressure and purified by HPLC to give the title compound(89 mg).

LCMS m/z=511.4 [M+H]⁺.

Example 1.288: Preparation of2-(((1s,4s)-4-((4-(3,4-Difluorophenyl)-5-((R)-3,4-dihydroxybutyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 170)

To a solution of regioisomers, tert-butyl2-(((1r,4s)-4-((4-bromo-3-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4s)-4-((4-bromo-5-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.254 mmol), in dioxane (1 mL), was added3,4-difluorophenylboronic acid (40.0 mg, 0.254 mmol), Pd(PPh₃)₄(14.65mg, 0.013 mmol) and a 2.0 M aqueous solution of K₂CO₃ (70.1 mg, 0.507mmol) at ambient temperature. The reaction was heated under microwave at120° C. for 1.5 h. The reaction was extracted with ethyl acetate andconcentrated under reduced pressure. The residue was treated with 4.0 MHCl in dioxane and was stirred for 5 h. The reaction was concentratedunder reduced pressure and purified by HPLC to give the title compound(72 mg). LCMS m/z=529.3 [M+H]⁺.

Example 1.289: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-5-((R)-3,4-dihydroxybutyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 171)

To a solution of regioisomers, tert-butyl2-(((1r,4s)-4-((4-bromo-3-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetateand tert-butyl2-(((1r,4s)-4-((4-bromo-5-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)acetate(150 mg, 0.254 mmol), in dioxane (l mL), were added3-chlorophenylboronic acid (39.7 mg, 0.254 mmol), Pd(PPh₃)₄(14.65 mg,0.013 mmol) and a 2.0 M aqueous solution of K₂CO₃ (70.1 mg, 0.507 mmol)at ambient temperature. The reaction was heated under microwave at 120°C. for 1.5 h. The reaction was extracted with ethyl acetate andconcentrated under reduced pressure. The residue was treated with 4.0 MHCl in dioxane and stirred for 5 h. The reaction was concentrated underreduced pressure and purified by HPLC to give the title compound (85mg). LCMS m/z=528.3 [M+H]⁺.

Example 1.290: Preparation of2-(((1s,4s)-4-((3-(Cyanomethylthio)-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 183) Step A: Preparation of2-(3,4-Diphenyl-1H-pyrazol-5-ylthio)acetonitrile

To a solution of 3,4-diphenyl-1H-pyrazole-5(4H)-thione (0.49 g, 1.981mmol) in DMF (5 mL), were added 2-bromoacetonitrile (0.253 g, 1.981mmol) and K₂CO₃ (0.274 g, 1.981 mmol) at room temperature. Afterstirring for 2 h, the reaction was poured into water and extracted withethyl acetate. The organic extract was dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified by columnchromatography to give the title compound (0.52 g). LCMS m/z=292.1

Step B: Preparation of(2-(((1s,4s)-4-((3-(Cyanomethylthio)-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of 2-(3,4-diphenyl-1H-pyrazol-5-ylthio)acetonitrile (330mg, 1.13 mmol) in DMF (2 mL), was added sodium hydride (27.2 mg, 1.133mmol) in 0° C. After stirring for 10 min, tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (467 mg, 1.13mmol) was added and the reaction was warmed to 40° C. After stirring for12 h, the reaction was poured into water and extracted with ethylacetate. The extract was dried over MgSO₄, concentrated under reducedpressure, and then treated with 4.0 M HCl in dioxane (5 mL). Afterstirring for 8 h, the mixture was concentrated under reduced pressureand purified by HPLC to give the title compound (78 mg). LCMS m/z=476.2[M+H]⁺.

Example 1.291: Preparation of2-(((1s,4s)-4-((5-(2-Methoxyethylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 189)

From 5-(2-methoxyethylthio)-3,4-diphenyl-1H-pyrazole and tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, the titlecompound was obtained by using similar method to the one described inExample 1.263. LCMS m/z=495.7 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.35-1.52 (m, 8H), 1.85 (m, 1H), 2.31 (m, 1H), 2.43 (t, J=2.5 Hz, 2H),2.61 (t, J=2.5 Hz, 2H), 3.05 (s, 3H), 3.46 (d, J=7.1 Hz, 2H), 3.98 (s,2H), 4.31 (d, J=7.2 Hz, 2H), 7.31-7.54 (m, 10H).

Example 1.292: Preparation of2-(((1s,4s)-4-((3-(2-Ethoxyethylthio)-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 185) Step A: Preparation of5-(2-Ethoxyethylthio)-3,4-diphenyl-1H-pyrazole

To a solution of 3,4-diphenyl-1H-pyrazole-5(4H)-thione (0.5 g, 1.981mmol) in DMF (5 mL), were added 1-bromo-2-ethoxyethane (0.303 g, 1.981mmol) and K₂CO₃(0.274 g, 1.981 mmol) at room temperature. After stirringfor 4 h, the reaction was poured into water and extracted with ethylacetate, which was dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by column chromatography to give thetitle compound (0.45 g). LCMS m/z=343.5 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.20 (t, J=7.1 Hz, 3H), 3.25 (m, 2H), 3.45 (m, 2H), 4.25(q, J=7.1 Hz, 2H), 7.25-7.56 (m, 10H), 13.0 (s, 1H).

Step B: Preparation of(2-(((1s,4s)-4-((3-(2-Ethoxyethylthio)-4,5-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of 5-(2-ethoxyethylthio)-3,4-diphenyl-1H-pyrazole (320 mg,0.986 mmol) in DMF (2 mL), was added sodium hydride (23.67 mg, 0.986mmol) at 0° C. After stirring for 10 min, tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (407 mg, 0.986mmol) was added and the reaction was warmed to 40° C. After stirring for12 h, the reaction was poured into water and extracted with ethylacetate. The extract was dried over MgSO₄ and concentrated under reducedpressure. The resulting residue was treated with 4.0 M HCl in dioxane (5mL) and stirred for 8 h. The reaction was concentrated under reducedpressure and purified by HPLC to give the title compound (70 mg). LCMSm/z=509.5 [M+H]⁺.

Example 1.293: Preparation of2-(((1s,4s)-4-((5-(2-Ethoxyethylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 186)

From 5-(2-ethoxyethylthio)-3,4-diphenyl-1H-pyrazole and tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, the titlecompound was obtained by using a similar method to the one described inExample 1.292. LCMS m/z=509.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.01 (t, J=7.1 Hz, 3H), 1.35-1.52 (m, 8H), 1.85 (m, 1H), 2.25 (m, 1H),2.41 (q, J=7.1 Hz, 2H), 2.60 (t, J=5.0 Hz, 2H), 3.25 (t, J=5.0 Hz, 2H),3.45 (d, J=7.1 Hz, 2H), 4.00 (s, 2H), 4.35 (d, J=7.2 Hz, 2H), 7.25-7.53(m, 10H).

Example 1.294: Preparation of2-(((1s,4s)-4-((5-(3-Hydroxypropylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 187) Step A: Preparation of3,4-Diphenyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethylthio)-1H-pyrazole

To a solution of 3-(4-bromo-3-phenyl-1H-pyrazol-5-yl)propan-1-ol (1.0 g,3.56 mmol) in THF (10 mL), was added 3,4-dihydro-2H-pyran (0.898 g,10.67 mmol) followed by PTSA (0.061 g, 0.356 mmol) at room temperature.After stirring for 12 h, the reaction was poured into water andextracted with ethyl acetate. The extract was dried over MgSO₄ andconcentrated under reduced pressure to give the title compound (1.12 g).LCMS m/z=381.2 [M+H]⁺.

Step B: Preparation of(2-(((1s,4s)-4-((5-(2-Hydroxyethylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of3,4-diphenyl-5-(3-(tetrahydro-2H-pyran-2-yloxy)propylthio)-1H-pyrazole(120 mg, 0.304 mmol) in DMF (2 mL), was added sodium hydride (7.30 mg,0.304 mmol) at 0° C. After stirring for 10 min, tert-butyl2-(((s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (125 mg, 0.304mmol) was added and the reaction was warmed to 40° C. After stirring for12 h, the reaction was poured into water and extracted with ethylacetate. The extract was concentrated under reduced pressure and treatedwith 4.0 M HCl dioxane (5 mL) for 8 h. The mixture was concentratedunder reduced pressure and purified by HPLC to give the title compound(105 mg). LCMS m/z=495.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.35-1.52 (m, 10OH), 1.83 (m, 1H), 2.22 (m, 1H), 2.46 (t, J=5.0 Hz, 2H),3.22 (t, J=5.0 Hz, 2H), 3.50 (d, J=7.1 Hz, 2H), 3.91 (s, 2H), 4.30 (d,J=7.2 Hz, 2H), 7.23-7.50 (m, 10H).

Example 2: Homogeneous Time-Resolved Fluorescence (HTRF®) Assay forDirect cAMP Measurement

Compounds were screened for agonists of the human prostacyclin (PGI2)receptor using the HTRF® assay for direct cAMP measurement (Gabriel etal., ASSAY and Drug Development Technologies, 1:291-303, 2003) andrecombinant CHO-K1 cells stably transfected with human prostacyclinreceptor. CHO-K1 cells were obtained from ATCC® (Manassas, Va.; Catalog# CCL-61). An agonist of the prostacyclin receptor was detected in HTRF®assay for direct cAMP measurement as a compound which increased cAMPconcentration. HTRF® assay also was used to determine EC₅₀ values forprostacyclin receptor agonists.

Principle of the Assay:

The HTRF® assay kit was purchased from Cisbio-US, Inc. (Bedford, Mass.;Catalog #62AM4PEC). The HTRF® assay supported by the kit is acompetitive immunoassay between endogenous cAMP produced by the CHO-K1cells and tracer cAMP labeled with the dye d2. The tracer binding isvisualized by a monoclonal anti-cAMP antibody labeled with Cryptate. Thespecific signal (i.e., fluorescence resonance energy transfer, FRET) isinversely proportional to the concentration of unlabeled cAMP in thestandard or sample.

Standard Curve:

The fluorescence ratio (665 nm/620 nm) of the standards (0.17 to 712 nMcAMP) included in the assay was calculated and used to generate a cAMPstandard curve according to the kit manufacturer's instructions. Thefluorescence ratio of the samples (test compound or compound buffer) wascalculated and used to deduce respective cAMP concentrations byreference to the cAMP standard curve.

Setup of the Assay:

The HTRF® assay was carried out using a two-step protocol essentiallyaccording to the kit manufacturer's instructions, in 20 μL total volumeper well in 384-well plate format (ProxiPlates; PerkinElmer, Fremont,Calif.; catalog #6008280). To each of the experimental wells wastransferred 3000 recombinant CHO-K1 cells in 5 μL assay buffer(phosphate buffered saline containing calcium chloride and magnesiumchloride (Invitrogen, Carlsbad, Calif.; catalog #14040) supplementedwith IBMX (100 μM) and rolipram (10 μM) (phosphodiesterase inhibitors;Sigma-Aldrich, St. Louis, Mo.; catalog #15879 and catalog #R6520,respectively) and 0.1% bovine serum albumin (BSA) fraction V(Sigma-Aldrich; catalog # A3059)), followed by test compound in 5 μLassay buffer or 5 μL assay buffer. The plate was then incubated at roomtemperature for 1 h. To each well was then added 5 μL cAMP-d2 conjugatein lysis buffer and 5 μL Cryptate conjugate in lysis buffer according tothe kit manufacturer's instructions. The plate was then furtherincubated at room temperature for 1 h, after which the assay plate wasread.

Assay Readout:

The HTRF® readout was accomplished using a PHERAstar (BMG LABTECH Inc.,Durham, N.C.) or EnVision™ (PerkinElmer, Fremont Calif.) microplatereader.

Certain compounds of the present invention and their correspondingactivity values are shown in TABLE B.

TABLE B human PGI2 receptor Compound No. EC₅₀ (nM) (HTRF ®) 90 7 111 16184 11 198 2

Certain other compounds of the invention had activity values rangingfrom about 1.3 nM to about 5 μM in this assay.

Example 3: Human Platelet Aggregation Inhibition Test

Blood collected from healthy human volunteers in aqueous trisodiumcitrate solution was centrifuged at 150 g for 15 min and the upper layerwas recovered to obtain platelet-rich plasma (PRP). The residual bloodwas centrifuged at 3000 g for 10 min and the supernatant was collectedas platelet-poor plasma (PPP). Platelet concentration in the PRP wasdetermined using the Z series Beckman Coulter particle counter (Beckman,Fullerton, Calif.) and adjusted to 250,000 platelets/μL using PPP. 480μL of PRP was pre-incubated at 37° C. and stirred at 1200 rpm with 10 μLaqueous test compound solution for 1 min prior to induction ofaggregation by the addition of 10 μL of aqueous adenosine diphosphate(ADP) solution to adjust the final ADP concentration in the PRP to1×10⁻⁵ M. The maximal amplitude of aggregation response within 3 min wasdetermined and measured in triplicate using the Chronolog model 490aggregometer (Chrono-log Corp., Havertown, Pa.). Percent inhibition ofaggregation was calculated from the maximum decrease in optical densityof the control (addition of water in place of the test compoundsolution) sample and of the samples containing test compound. The testcompound was added to adjust the final concentration to the range 10⁻⁹to 10⁻⁴ M, and IC₅₀ values were determined by inhibition percentage ofaggregation at each concentration. The results are shown in Table C.

TABLE C Compound No. human PRP IC₅₀ (nM) 184 20 111 28 146 70 135 220

Certain other compounds of the invention had activity values rangingfrom about 10.3 nM to about 810 nM in this assay.

It is apparent that the compounds of the present invention markedlyinhibit platelet aggregation in human PRP.

Example 4: Rat Model of Pulmonary Arterial Hypertension

Animals:

Male Wistar rats (100-150 g at start of study) (Charles RiverLaboratories, Wilmington, Mass.) were housed two per cage and maintainedin a humidity—(40-60%) and temperature—(68-72° F.) controlled facilityon a 12 hr:12 hr light/dark cycle (lights on at 6:30 am) with freeaccess to food (Harlan Teklad, Orange Calif., Rodent Diet 8604) andwater. Rats were allowed one week of habituation to the animal facilitybefore testing.

Rat Monocrotaline Model:

The rat monocrotaline (MCT) model is a standard and well-accepted modelof pulmonary arterial hypertension. MCT induces acute pulmonaryendothelial damage associated with pulmonary vascular inflammation.Subsequently, pulmonary artery smooth muscle cells proliferate,occluding small pulmonary vessels and leading to severe pulmonaryarterial hypertension including right ventricular hypertrophy. (See,e.g., Schermuly et al., Circ. Res., 2004, 94:1101-1108.)

Rats were randomly given a single subcutaneous injection of either 60mg/kg MCT (Sigma, St. Louis, Mo.) or 0.9% saline (sham) and assigned toreceive oral administration of 20% hydroxypropyl beta-cyclodextrin(vehicle) or test compound (30 mg/kg; FIGS. 1 and 2). 10-11 rats wereused per treatment group. 24 h following MCT administration, testcompound or vehicle was administered by oral gavage twice a day for 21consecutive days. Heart chamber weights were measured on Day 22. Ratswere anesthetized with intraperitoneal pentobarbital (50 mg/kg), thechest cavity was opened and the heart was excised. The right ventriclewas dissected free from the septum and left ventricle and both partswere weighed. The ratio of right ventricular (RV) weight to leftventricle plus septum (LV+S) weight (this ratio is indicated as“RV/(LV+S)” in FIGS. 1 and 2) was calculated as an index of thehypertrophic response to the induced pulmonary arterial hypertensionand, as such, as an index of a test compound's therapeutic efficacy forpulmonary arterial hypertension.

It is apparent from inspection of FIGS. 1 and 2 that oral administrationof Compounds 14 and 31 inhibited the hypertrophic response to theinduced pulmonary arterial hypertension and, as such, evidencedtherapeutic efficacy for pulmonary arterial hypertension.

Those skilled in the art will recognize that various modifications,additions, substitutions and variations to the illustrative examples setforth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention. All documents referenced above, including, but not limitedto, printed publications and provisional and regular patentapplications, are incorporated herein by reference in their entirety.

1-49. (canceled)
 50. A process for preparing a pharmaceuticalcomposition comprising admixing a compound selected from the followingcompounds and pharmaceutically acceptable salts, solvates, and hydratesthereof:2-(((1s,4s)-4-((4-(3-methoxyphenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(3-methoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((5-(methylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(3-chlorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((5-ethyl-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((5-(methylthio)-4-(5-methylthiophen-2-yl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid:2-(((1s,4s)-4-((3-(2-fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(4-chloro-2-fluorophenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((5-(2-hydroxyethylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(4-fluorophenyl)-5-(2-hydroxyethylthio)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid: and a pharmaceutically acceptable carrier.
 51. The process ofclaim 50, wherein the compound is selected from the following compoundsand pharmaceutically acceptable salts, solvates, and hydrates thereof:2-(((1s,4s)-4-((4-(3-methoxyphenyl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid.
 52. The process of claim 50, wherein the compound is selected fromthe following compounds and pharmaceutically acceptable salts, solvates,and hydrates thereof:2-(((1s,4s)-4-((4-(3-methoxyphenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid.
 53. The process of claim 50, wherein the compound is selected fromthe following compounds and pharmaceutically acceptable salts, solvates,and hydrates thereof:2-(((1s,4s)-4-((5-(methylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid.
 54. The process of claim 50, wherein the compound is selected fromthe following compounds and pharmaceutically acceptable salts, solvates,and hydrates thereof:2-(((1s,4s)-4-((4-(3-chlorophenyl)-5-(methylthio)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid.
 55. The process of claim 50, wherein the compound is selected fromthe following compounds and pharmaceutically acceptable salts, solvates,and hydrates thereof:2-(((1s,4s)-4-((5-ethyl-4-(3-methoxyphenyl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid.
 56. The process of claim 50, wherein the compound is selected fromthe following compounds and pharmaceutically acceptable salts, solvates,and hydrates thereof:2-(((1s,4s)-4-((5-(methylthio)-4-(5-methylthiophen-2-yl)-3-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid.
 57. The process of claim 50, wherein the compound is selected fromthe following compounds and pharmaceutically acceptable salts, solvates,and hydrates thereof:2-(((1s,4s)-4-((3-(2-fluoro-4-methylphenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid.
 58. The process of claim 50, wherein the compound is selected fromthe following compounds and pharmaceutically acceptable salts, solvates,and hydrates thereof:2-(((1s,4s)-4-((3-(4-chloro-2-fluorophenyl)-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid.
 59. The process of claim 50, wherein the compound is selected fromthe following compounds and pharmaceutically acceptable salts, solvates,and hydrates thereof:2-(((1s,4s)-4-((5-(2-hydroxyethylthio)-3,4-diphenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid.
 60. The process of claim 50, wherein the compound is selected fromthe following compounds and pharmaceutically acceptable salts, solvates,and hydrates thereof:2-(((1s,4s)-4-((3-(4-fluorophenyl)-5-(2-hydroxyethylthio)-4-phenyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methoxy)aceticacid.
 61. A process for the preparation of a compound selected fromcompounds of the formula

and pharmaceutically acceptable salts, solvates and hydrates thereof:wherein: R², R³, and R⁴ are each independently selected from: H, C₁-C₆alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylthio, aryl, C₃-C₇ cycloalkyl and heteroaryl; wherein said C₁-C₆alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylthio, aryl, C₃-C₇ cycloalkyl and heteroaryl are each optionallysubstituted with one or more groups selected from: C₁-C₆ alkoxy, C₁-C₆alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, amino,aryl, carboxamide, cyano, C₁-C₆ haloalkyl, halogen and hydroxy; or R²and R³ together with the pyrazole ring to which they are both attachedto form a tricyclic heteroaryl; and R⁴ is selected from: H, C₁-C₆alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylthio, aryl, C₃-C₇ cycloalkyl and heteroaryl; wherein said C₁-C₆alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylthio, aryl, C₃-C₇ cycloalkyl and heteroaryl are each optionallysubstituted with one or more groups selected from: C₁-C₆ alkoxy, C₁-C₆alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, amino,aryl, cyano, C₁-C₆ haloalkyl, halogen and hydroxyl, the processcomprising converting a compound of the Formula Ia

wherein R¹ is C1-C₆ alkyl to the compound of the formula